Naphthyridinedione derivatives

ABSTRACT

The invention relates to compound of the formula (I′) 
                         
or a salt thereof, wherein the substituents are as defined in the specification; to its preparation, to its use as medicament and to medicaments comprising it.

The invention relates to naphthyridinedione derivatives, to theirpreparation, to their use as medicaments and to medicaments comprisingthem.

Many human genetic diseases are caused by nonsense mutations (seeKeeling et al, WIREs RNA, 2011, 2, 837-852; Linde et al, Trends inGenetics, 2008, 24(11), 552-563; and Rose et al, Pharmacology &Therapeutics, 2012 136(2), 227-266).

A nonsense mutation is a genetic mutation leading to the transformationof a sense codon into a premature termination codon (hereinafter PTC)upstream from the normal termination codon.

Eukaryotic termination codons are UAA, UAG or UGA.

The normal termination codon stops gene translation and enablesfull-length, wild type protein synthesis. A PTC prevents such wild typeprotein synthesis and leads to truncated, in many cases inactive,proteins. The resulting partial/total lack of protein leads to thepathology of the disease caused by such a nonsense mutation.

Nonsense mutations can be in-frame mutations, e.g. single nucleic acidexchanges transforming a single codon into a PTC, or frameshiftmutations, e.g. a single nucleic acid insertion/deletion transformingthe affected codon into a PTC.

A compound being able to suppress the effect of a nonsense mutation isherein called a “nonsense mutation suppressor”.

One mechanism to suppress the effect of nonsense mutations is toincrease the rate of readthrough events during translation. A compoundhaving this mechanism of action is herein called a “readthroughactivator”. In a readthrough event, an aminoacyl tRNA being near-cognateis used to recode a termination codon into a sense codon. Under basalconditions, the recoding of a PTC into a sense codon occurs in less than1% of translation events, while suppression of a normal stop codonoccurs at a frequency of <0.1%. Amino acids inserted by recoding willnot necessarily be identical to the corresponding amino acids of thewild-type protein; however many amino acid substitutions arefunctionally tolerated. Thus, a protein produced by readthroughactivation may possess activity strongly similar to the wild-typeprotein. Consequently, by increasing the rate of PTC-recoding enoughfunctional protein may be restored to provide a therapeutic benefit topatients carrying a nonsense mutation.

Another mechanism to suppress the effect of nonsense mutations is toinhibit nonsense-mediated mRNA decay (NMD). A compound having thismechanism of action is herein called a “NMD inhibitor”. NMD regulatesthe total level of PTC-bearing transcripts: it detects and degrades suchtranscripts to prevent synthesis of truncated proteins which might benonfunctional or deleterious owing to dominant-negative orgain-of-function effects. Inhibition of NMD increases the number oftranscripts available which could also be a mechanism to restore enoughfunctional protein for a therapeutic benefit.

Compounds described as nonsense mutation suppressors are certainaminoglycoside antibiotics, e.g. in WO2007113841, and certain1,2,4-oxadiazole benzoic acids, e.g. in WO2004091502 and a compoundcommonly called amlexanox (WO2012016930). WO2009086303 describes agentsfor increasing lifespan. WO96/28444 describes dihydropyrimidoquinolinonecompounds as tyrosine kinase inhibitors.

Other pyridopyrimidinedione derivatives are described in WO199208719, inSynthetic Communications, 1999, 29(22), 3919-3937, in Monatshefte fuerChemie, 1996, 127(8/9), 917-925.

Nonsense mutation suppressors are considered to be useful in thetreatment of a wide range of diseases caused by nonsense mutations.Prominent examples of diseases caused by nonsense mutations are diseasescaused by nonsense mutations in lysosomal enzymes, e.g.mucopolysaccharidosis I (Hurler syndrome) caused by nonsense mutationsin -L-iduronidase; hemophilia A or hemophilia B caused by nonsensemutations in coagulation factors 7, 8 or 9; cystic fibrosis caused bynonsense mutations in the chloride channel CFTR; diseases caused bynonsense mutations in structural proteins, e.g. Duchenne or BeckerMuscle Dystrophy caused by nonsense mutations in dystrophin; or cancercaused by nonsense mutations in APC or p53.

There is a need to provide new nonsense mutation suppressors that aregood drug candidates. In particular, preferred compounds should bepotent nonsense mutation suppressors whilst showing little potency inother drug target assays, e.g. GPCR or ion channel assays. They shouldexhibit a low binding to plasma proteins. They should be well absorbedfrom the gastrointestinal tract, be sufficiently metabolically stableand possess favorable pharmacokinetic properties. They should benon-toxic and demonstrate few side-effects. Furthermore, the ideal drugcandidate will be able to exist in a physical form that is stable,non-hygroscopic and easily formulated.

The compounds of the invention are nonsense mutation suppressors and aretherefore potentially useful in the treatment of a wide range ofdiseases caused by nonsense mutations, particularly wherein the diseaseis selected from hemophilia A, hemophilia B, cystic fibrosis,mucopolysaccharidosis I, Duchenne Muscle Dystrophy, Becker MuscleDystrophy, loss of APC caused cancer and loss of p53 caused cancer.

In a first aspect, the invention relates to a compound of formula (I′)in free form or in pharmaceutically acceptable salt form

wherein

-   -   a) R₁ is a five- to seven-membered monocyclic saturated or        unsaturated non-aromatic ring system, wherein said ring system        may contain from 1 to 4 hetero atoms selected from nitrogen,        oxygen and sulfur, and wherein said ring system may be        substituted once or more than once by R₆;        -   and        -   R₂ is C₂₋₆alkyl which may be substituted once or more than            once by R₇;        -   or R₂ is —X₁—R₈; —X₁— is —O —, —S— or —N(R₉)—; R₉ is            hydrogen or C₁₋₄alkyl; and R₈ is C₁₋₆alkyl which may be            substituted once or more than once by R₁₀;        -   or R₂ is a three- to seven-membered monocyclic aromatic,            saturated or unsaturated non-aromatic ring system, wherein            said ring system may contain from 1 to 4 hetero atoms            selected from nitrogen, oxygen and sulfur, and wherein said            ring system may be substituted once or more than once by            R₁₁;            or    -   b) R₁ is

-   -   -   wherein the phenyl ring is attached via the bond marked with            an asterisk;        -   each R₁₂ independently is hydrogen, halogen, hydroxyl,            amino, cyano, nitro, C₁₋₄alkyl, C₁₋₄halogenalkyl,            C₁₋₄hydroxyalkyl, C₁₋₄alkoxy-C₁₋₄alkyl, amino-C₁₋₄alkyl,            C₁₋₄alkyl-amino-C₁₋₄alkyl, di(C₁₋₄alkyl)-amino-C₁₋₄alkyl,            C₁₋₄alkoxy, C₁₋₄halogenalkoxy, C₁₋₄alkylamino or            di(C₁₋₄alkyl)amino; or C₃₋₆cycloalkyl, wherein one carbon            atom may be replaced by an oxygen atom, wherein the            C₃₋₆cycloalkyl may be attached directly or via a            C₁₋₂alkylene, and wherein the C₃₋₆cycloalkyl may be            substituted once or more than once by halogen;        -   and        -   R₂ is C₂₋₇alkyl which may be substituted once or more than            once by R₁₃;        -   or R₂ is —X₂—R₁₄; —X₂— is —O —, —S— or —N(R₁₅)—; R₁₅ is            hydrogen or C₁₋₄alkyl; and R₁₄ is C₁₋₆alkyl which may be            substituted once or more than once by R₁₆;        -   or R₂ is a three- to seven-membered monocyclic saturated or            unsaturated non-aromatic ring system, wherein said ring            system may contain from 1 to 4 hetero atoms selected from            nitrogen, oxygen and sulfur, and wherein said ring system            may be substituted once or more than once by R₁₇;            or

    -   c) R₁ is a ring selected from pyrrolyl, pyrazolyl, thiophenyl or        pyridin-2-yl, which ring may be substituted by C₁₋₃alkyl;        -   and        -   R₂ is C₂₋₇alkyl which may be substituted once or more than            once by R₁₃;        -   or R₂ is —X₂—R₁₄; —X₂— is —O —, —S— or —N(R₁₅)—; R₁₅ is            hydrogen or C₁₋₄alkyl; and R₁₄ is C₁₋₆alkyl which may be            substituted once or more than once by R₁₆;        -   or R₂ is a three- to seven-membered monocyclic saturated or            unsaturated non-aromatic ring system, wherein said ring            system may contain from 1 to 4 hetero atoms selected from            nitrogen, oxygen and sulfur, and wherein said ring system            may be substituted once or more than once by R₁₇;            R₃ is hydrogen or —CH₂R₁₈;            R₁₈ is hydrogen, C₁₋₄alkyl, C₂₋₆alkenyl, C₃₋₆cycloalkyl,            C₁₋₃alkoxyC₁₋₃alkyl, hydroxyC₁₋₃alkyl or aminoC₁₋₃alkyl;            R₄ and R₅ are independently selected from hydrogen,            C₁-C₃alkyl;            or            R₄ and R₅ together with the bond to which they are attached            form a ring which is selected from

    -   5- to 7-membered monocyclic non-aromatic carbocyclic ring which        may be substituted once or more than once by R₁₉;

    -   a thiophene ring, which may be substituted once by R₂₀;

which is fused to the rest of the molecule by the bond marked with twoasterisks;R₁₉ and R₂₀ are independently selected from halogen, C₁-C₃alkyl;R₂₁ is hydrogen, halogen, hydroxyl, amino, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy-C₁₋₄alkyl,amino-C₁₋₄alkyl, C₁₋₄alkyl-amino-C₁₋₄alkyl,di(C₁₋₄alkyl)-amino-C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄halogenalkoxy,C₁₋₄alkylamino or di(C₁₋₄alkyl)amino; or a three- to seven-memberedmonocyclic aromatic, saturated or unsaturated non-aromatic ring system,wherein said ring system may contain from 1 to 4 hetero atoms selectedfrom nitrogen, oxygen and sulfur, wherein said ring system may beattached directly or via a C₁₋₂alkylene, and wherein said ring systemmay be substituted once or more than once by R₂₃; orR₃ and R₂₁ taken together are —CH₂—CH₂—;R₂₂ is hydrogen, halogen, hydroxyl, cyano, C₁₋₄alkyl, C₁₋₄halogenalkyl,C₁₋₄hydroxyalkyl, C₁₋₄alkoxy-C₁₋₄alkyl, amino-C₁₋₄alkyl,C₁₋₄alkyl-amino-C₁₋₄alkyl, di(C₁₋₄alkyl)-amino-C₁₋₄alkyl, C₂₋₄alkenyl,C₂₋₄alkinyl, C₁₋₄alkoxy or C₁₋₄halogenalkoxy; or C₃₋₄cycloalkyl, whereinone carbon atom may be replaced by an oxygen atom, wherein theC₃₋₄cycloalkyl may be attached directly or via a C₁₋₂alkylene, andwherein the C₃₋₄cycloalkyl may be substituted once or more than once byhalogen;R₆, R₁₁, R₁₇ and R₂₃ each independently is halogen, hydroxyl, amino,cyano, nitro, C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄hydroxyalkyl,amino-C₁₋₄alkyl, C₁₋₄alkyl-amino-C₁₋₄alkoxy, C₁₋₄halogenalkoxy,C₁₋₄alkylamino or di(C₁₋₄alkyl)amino;or C₃₋₆cycloalkyl, wherein one carbon atom may be replaced by an oxygenatom, wherein the C₃₋₆cycloalkyl may be attached directly or via aC₁₋₂alkylene, and wherein the C₃₋₆cycloalkyl may be substituted once ormore than once by halogen;or two R₆, R₁₁, R₁₇ and R₂₃ at the same ring atom together are oxo;or two R₆, R₁₁, R₁₇ and R₂₃ at the same ring carbon atom together withsaid carbon atom form a C₃₋₆cycloalkyl;R₇, R₁₀, R₁₃ and R₁₆ each independently is halogen, hydroxyl, amino,cyano, nitro, C₁₋₄alkoxy, C₁₋₄halogenalkoxy, C₁₋₄alkylamino ordi(C₁₋₄alkyl)amino;or C₃₋₆cycloalkyl, wherein one carbon atom may be replaced by an oxygenatom, wherein the C₃₋₆cycloalkyl may be attached directly or via aC₁₋₂alkylene, and wherein the C₃₋₆cycloalkyl may be substituted once ormore than once by halogen;or two R₇, R₁₀, R₁₃ or R₁₆ at the same carbon atom together are oxo;or two R₇, R₁₀, R₁₃ or R₁₆ at the same carbon atom together with saidcarbon atom form a C₃₋₆cycloalkyl;R₂₄ is hydrogen or halogen.

In an aspect, the invention relates to a compound of formula (I) in freeform or in pharmaceutically acceptable salt form

wherein

-   -   a) R₁ is a five- to seven-membered monocyclic saturated or        unsaturated non-aromatic ring system, wherein said ring system        may contain from 1 to 4 hetero atoms selected from nitrogen,        oxygen and sulfur, and wherein said ring system may be        substituted once or more than once by R₆;        -   and        -   R₂ is C₂₋₆alkyl which may be substituted once or more than            once by R₇;        -   or R₂ is —X₁—R₈; —X₁— is —O—, —S— or —N(R₉)—; R₉ is hydrogen            or C₁₋₄alkyl; and R₈ is C₁₋₆alkyl which may be substituted            once or more than once by R₁₀;        -   or R₂ is a three- to seven-membered monocyclic aromatic,            saturated or unsaturated non-aromatic ring system, wherein            said ring system may contain from 1 to 4 hetero atoms            selected from nitrogen, oxygen and sulfur, and wherein said            ring system may be substituted once or more than once by            R₁₁;            or    -   b) R₁ is

-   -   -   wherein the phenyl ring is attached via the bond marked with            an asterisk;        -   each R₁₂ independently is hydrogen, halogen, hydroxyl,            amino, cyano, nitro, C₁₋₄alkyl, C₁₋₄halogenalkyl,            C₁₋₄hydroxyalkyl, C₁₋₄alkoxy-C₁₋₄alkyl, amino-C₁₋₄alkyl,            C₁₋₄alkyl-amino-C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄halogenalkoxy,            C₁₋₄alkylamino or di(C₁₋₄alkyl)amino; or C₃₋₆cycloalkyl,            wherein one carbon atom may be replaced by an oxygen atom,            wherein the C₃₋₆cycloalkyl may be attached directly or via a            C₁₋₂alkylene, and wherein the C₃₋₆cycloalkyl may be            substituted once or more than once by halogen;        -   and        -   R₂ is C₂₋₇alkyl which may be substituted once or more than            once by R₁₃;        -   or R₂ is —X₂—R₁₄; —X₂— is —O—, —S— or —N(R₁₅)—; R₁₅ is            hydrogen or C₁₋₄alkyl; and R₁₄ is C₁₋₆alkyl which may be            substituted once or more than once by R₁₆;        -   or R₂ is a three- to seven-membered monocyclic saturated or            unsaturated non-aromatic ring system, wherein said ring            system may contain from 1 to 4 hetero atoms selected from            nitrogen, oxygen and sulfur, and wherein said ring system            may be substituted once or more than once by R₁₇;            or

    -   c) R₁ is a ring selected from pyrazolyl, thiophenyl or        pyridin-2-yl, which ring may be substituted by C₁₋₃alkyl;        -   and        -   R₂ is C₂₋₇alkyl which may be substituted once or more than            once by R₁₃;        -   or R₂ is —X₂—R₁₄; —X₂— is —O—, —S— or —N(R₁₅)—; R₁₅ is            hydrogen or C₁₋₄alkyl; and R₁₄ is C₁₋₆alkyl which may be            substituted once or more than once by R₁₆;        -   or R₂ is a three- to seven-membered monocyclic saturated or            unsaturated non-aromatic ring system, wherein said ring            system may contain from 1 to 4 hetero atoms selected from            nitrogen, oxygen and sulfur, and wherein said ring system            may be substituted once or more than once by R₁₇;            R₃ is hydrogen or —CH₂R₁₈;            R₁₈ is hydrogen, C₁₋₄alkyl, C₂₋₆alkenyl, C₃₋₆cycloalkyl,            C₁₋₃alkoxyC₁₋₃alkyl, hydroxyC₁₋₃alkyl or aminoC₁₋₃alkyl;            R₄ and R₅ are independently selected from hydrogen,            C₁-C₃alkyl;            or            R₄ and R₅ together with the bond to which they are attached            form a ring which is selected from

    -   5- to 7-membered monocyclic non-aromatic carbocyclic ring which        may be substituted once or more than once by R₁₉;

    -   a thiophene ring, which may be substituted once by R₂₀;

which is fused to the rest of the molecule by the bond marked with twoasterisks;R₁₉ and R₂₀ are independently selected from halogen, C₁-C₃alkyl;R₂₁ is hydrogen, halogen, hydroxyl, amino, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy-C₁₋₄alkyl,amino-C₁₋₄alkyl, C₁₋₄alkyl-amino-C₁₋₄alkyl,di(C₁₋₄alkyl)-amino-C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄halogenalkoxy,C₁₋₄alkylamino or di(C₁₋₄alkyl)amino; or a three- to seven-memberedmonocyclic aromatic, saturated or unsaturated non-aromatic ring system,wherein said ring system may contain from 1 to 4 hetero atoms selectedfrom nitrogen, oxygen and sulfur, wherein said ring system may beattached directly or via a C₁₋₂alkylene, and wherein said ring systemmay be substituted once or more than once by R₂₃;orR₃ and R₂₁ taken together are —CH₂—CH₂—;R₂₂ is hydrogen, halogen, hydroxyl, cyano, C₁₋₄alkyl, C₁₋₄halogenalkyl,C₁₋₄hydroxyalkyl, C₁₋₄alkoxy-C₁₋₄alkyl, di(C₁₋₄alkyl)-amino-C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkinyl, C₁₋₄alkoxy or C₁₋₄halogenalkoxy; orC₃₋₄cycloalkyl, wherein one carbon atom may be replaced by an oxygenatom, wherein the C₃₋₄cycloalkyl may be attached directly or via aC₁₋₂alkylene, and wherein the C₃₋₄cycloalkyl may be substituted once ormore than once by halogen;R₆, R₁₁, R₁₇ and R₂₃ each independently is halogen, hydroxyl, amino,cyano, nitro, C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄hydroxyalkyl,C₁₋₄alkoxy-C₁₋₄alkyl, amino-C₁₋₄alkyl, C₁₋₄alkyl-amino-C₁₋₄alkyl,C₁₋₄alkoxy, C₁₋₄halogenalkoxy, C₁₋₄alkylamino or di(C₁₋₄alkyl)amino;or C₃₋₆cycloalkyl, wherein one carbon atom may be replaced by an oxygenatom, wherein the C₃₋₆cycloalkyl may be attached directly or via aC₁₋₂alkylene, and wherein the C₃₋₆cycloalkyl may be substituted once ormore than once by halogen;or two R₆, R₁₁, R₁₇ and R₂₃ at the same ring atom together are oxo;or two R₆, R₁₁, R₁₇ and R₂₃ at the same ring carbon atom together withsaid carbon atom form a C₃₋₆cycloalkyl;R₇, R₁₀, R₁₃ and R₁₆ each independently is halogen, hydroxyl, amino,cyano, nitro, C₁₋₄alkoxy, C₁₋₄halogenalkoxy, C₁₋₄alkylamino ordi(C₁₋₄alkyl)amino;or C₃₋₆cycloalkyl, wherein one carbon atom may be replaced by an oxygenatom, wherein the C₃₋₆cycloalkyl may be attached directly or via aC₁₋₂alkylene, and wherein the C₃₋₆cycloalkyl may be substituted once ormore than once by halogen;or two R₇, R₁₀, R₁₃ or R₁₆ at the same carbon atom together are oxo;or two R₇, R₁₀, R₁₃ or R₁₆ at the same carbon atom together with saidcarbon atom form a C₃₋₆cycloalkyl.

In another aspect, the invention relates to a compound of formula (Ia′)in free form or in a pharmaceutically acceptable salt form which is

wherein R₁, R₂, R₃, R₂₁, R₂₂, R₂₄ are as defined herein in relation to acompound of formula (I′).

In another aspect, the invention relates to a compound of formula (Ia)in free form or in a pharmaceutically acceptable salt form which is

wherein R₁, R₂, R₃, R₂₁ and R₂₂ are as defined herein in relation to acompound of formula (I).

In a third aspect, the invention relates to a compound of formula (Ib)in free form or in a pharmaceutically acceptable salt form which is

wherein R₁, R₂, R₃, R₄ and R₅ are as defined herein in relation to acompound of formula (I).

Unless specified otherwise, the term “compounds of the invention” refersto compounds of formula (I), (I′), (Ia), (Ia′) and (Ib); salts of thecompounds; hydrates or solvates of the compounds and/or salts; as wellas all stereoisomers (including diastereoisomers), tautomers andisotopically labeled compounds (including deuterium substitutions); aswell as inherently formed moieties (e.g. polymorphs, solvates and/orhydrates).

Unless indicated otherwise, the expressions used in this invention havethe following meaning:

“Alkyl” represents a straight-chain or branched-chain alkyl group and,for example, may be methyl, ethyl, n- or iso-propyl or n-, iso-, sec- ortert-butyl; C₂₋₇alkyl preferably represents a straight-chain orbranched-chain C₂₋₄alkyl with particular preference given to ethyl,n-propyl, iso-propyl and tert-butyl. C₁₋₄alkyl preferably represents astraight-chain or branched-chain C₁₋₃alkyl with particular preferencegiven to methyl, ethyl, n-propyl and iso-propyl.

Each alkyl part of “alkoxy”, “halogenalkyl”, “hydroxyalkyl”,“aminoalkyl”, “alkoxyalkyl” and so on shall have the same meaning asdescribed in the above-mentioned definition of “alkyl”, especiallyregarding linearity and preferential size, unless the size is furtherspecified.

“C₃₋₆cycloalkyl” represents a saturated alicyclic moiety having fromthree to six carbon atoms. This term refers to groups such ascyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

A substituent being substituted “once or more than once”, e.g. asdefined in connection with R₁, is preferably substituted by one to threesubstituents. Thus, “once or more than once” includes but is not limitedto one, two or three substituents.

Halogen is generally fluorine, chlorine, bromine or iodine; preferablyfluorine, chlorine or bromine. Halogenalkyl groups preferably have achain length of 1 to 4 carbon atoms and are, for example, fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl,pentafluoroethyl, 1,1-difluoro-2,2,2-trichloroethyl,2,2,2-trichloroethyl, 1,1,2,2-tetrafluoroethyl,2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl or2,2,3,4,4,4-hexafluorobutyl.

In the context of the invention, the definition of R₁ as a “five- toseven-membered monocyclic saturated or unsaturated non-aromatic ringsystem, wherein said ring system may contain from 1 to 4 hetero atoms”encompasses five- to seven-membered monocyclic non-aromatic hydrocarbongroups and heterocyclic ring systems of the same sizes.

In the context of the invention, the definition of R₂ or R₄ as a “three-to seven-membered monocyclic aromatic, saturated or unsaturatednon-aromatic ring system, wherein said ring system may contain from 1 to4 hetero atoms” encompasses three- to seven-membered monocyclic aromaticor non-aromatic hydrocarbon groups and aromatic or non-aromaticheterocyclic ring systems of the same sizes.

Examples of heterocyclic ring systems are: pyrrole, pyrroline,pyrrolidine, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline,imidazolidine, triazole, triazoline, triazolidine, tetrazole, furane,dihydrofurane, tetrahydrofurane, oxadiazole, dioxolane, thiophene,dihydrothiophene, tetrahydrothiophene, oxazole, oxazoline, oxazolidine,isoxazole, isoxazoline, isoxazolidine, thiazole, thiazoline,thiazolidine, isothiazole, isothiazoline, isothiazolidine, thiadiazole,thiadiazoline, thiadiazolidine, pyridine, piperidine, pyridazine,pyrazine, pyrimidine, piperazine, triazine, pyrane, tetrahydropyrane,thiopyrane, tetrahydrothiopyrane, oxazine, thiazine, morpholine.

Compounds of formula (I′), (I), (Ia), (Ia) or (Ib) may exist inoptically active form or in form of mixtures of optical isomers, e.g. inform of racemic mixtures or diastereomeric mixtures. In particular,asymmetrical carbon atom(s) may be present in the compounds of formula(I′), (I), (Ia), (Ia) or (Ib) and their salts. Unless otherwise providedherein, all optical isomers and their mixtures, including the racemicmixtures, are embraced by the invention.

As used herein, the term “isomers” refers to different compounds thathave the same molecular formula but differ in arrangement andconfiguration of the atoms. Also as used herein, the term “an opticalisomer” or “a stereoisomer” refers to any of the various stereo isomericconfigurations which may exist for a given compound of the invention andincludes geometric isomers. It is understood that a substituent may beattached at a chiral center of a carbon atom. The term “chiral” refersto molecules which have the property of non-superimposability on theirmirror image partner, while the term “achiral” refers to molecules whichare superimposable on their mirror image partner. Therefore, theinvention includes enantiomers, diastereomers or racemates of thecompound. “Enantiomers” are a pair of stereoisomers that arenon-superimposable mirror images of each other. A 1:1 mixture of a pairof enantiomers is a “racemic” mixture. The term is used to designate aracemic mixture where appropriate. “Diastereoisomers” are stereoisomersthat have at least two asymmetric atoms, but which are not mirror-imagesof each other. The absolute stereochemistry is specified according tothe Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomerthe stereochemistry at each chiral carbon may be specified by either Ror S. Resolved compounds whose absolute configuration is unknown can bedesignated (+) or (−) depending on the direction (dextro- orlevorotatory) which they rotate plane polarized light at the wavelengthof the sodium D line. The compounds described herein may contain one ormore asymmetric centers and may thus give rise to enantiomers,diastereomers, and other stereoisomeric forms that may be defined, interms of absolute stereochemistry, as (R)- or (S)-. Unless otherwiseprovided herein, the invention is meant to include all such possibleisomers, including racemic mixtures, optically pure forms andintermediate mixtures. Optically active (R)- and (S)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques.

If the compound contains a double bond, the substituent may be E or Zconfiguration.

If the compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis- or trans-configuration.

Any asymmetric atom (e.g. carbon or the like) of the compound(s) of theinvention can be present in racemic or enantiomerically enriched, forexample the (R)-, (S)- or (R,S)-configuration. In certain embodiments,each asymmetric atom has at least 50% enantiomeric excess, at least 60%enantiomeric excess, at least 70% enantiomeric excess, at least 80%enantiomeric excess, at least 90% enantiomeric excess, at least 95%enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or(S)-configuration. Substituents at atoms with unsaturated bonds may, ifpossible, be present in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein, a compound of the invention can be in theform of one of the possible isomers, rotamers, atropisomers, tautomersor mixtures thereof, for example, as substantially pure geometric (cisor trans) isomers, diastereomers, optical isomers (antipodes), racematesor mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the invention into their opticalantipodes, e.g., by fractional crystallization of a salt formed with anoptically active acid, e.g., tartaric acid, dibenzoyl tartaric acid,diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelic acid,malic acid or camphor-10-sulfonic acid. Racemic products can also beresolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Depending on substituent definition, compounds of formula (I′), (I),(Ia′), (Ia) or (Ib) may occur in various tautomeric forms. Alltautomeric forms of the compounds of formula (I) are embraced by theinvention.

For example, compounds of formula (I), in which R₁, R₂, R₄ and R₅ are asdefined under formula (I), and R₃ is hydrogen, may exist in tautomericforms (I-1), (I-2) or (I-3):

As used herein, the terms “salt” or “salts” refers to an acid additionor base addition salt of a compound of the invention. “Salts” include inparticular “pharmaceutically acceptable salts”. The term“pharmaceutically acceptable salts” refers to salts that retain thebiological effectiveness and properties of the compounds of thisinvention and, which typically are not biologically or otherwiseundesirable. The compounds of the invention may be capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

The pharmaceutically acceptable salts of the invention can besynthesized from a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, use of non-aqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile is desirable, wherepracticable. Lists of additional suitable salts can be found, e.g., in“Remington's Pharmaceutical Sciences”, 20th ed., Mack PublishingCompany, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

When both a basic group and an acid group are present in the samemolecule, the compounds of the invention may also form internal salts,e.g., zwitterionic molecules.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F ³¹F, ³²P, ³⁵S, ³⁶Cl, ¹²⁵Irespectively. The invention includes various isotopically labeledcompounds as defined herein, for example those into which radioactiveisotopes, such as ³H and ¹⁴C, or those into which non-radioactiveisotopes, such as ²H and ¹³C are present. Such isotopically labelledcompounds are useful in metabolic studies (with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques,such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F labeled compound may be particularly desirable forPET or SPECT studies. Isotopically-labeled compounds of formula (I′),(I), (Ia), (Ia) or (Ib) can generally be prepared by conventionaltechniques known to those skilled in the art or by processes analogousto those described in the accompanying Examples and Preparations usingan appropriate isotopically-labeled reagents in place of the non-labeledreagent previously employed.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the formula (I′), (I), (Ia), (Ia) or (Ib).The concentration of such a heavier isotope, specifically deuterium, maybe defined by the isotopic enrichment factor. The term “isotopicenrichment factor” as used herein means the ratio between the isotopicabundance and the natural abundance of a specified isotope. If asubstituent in a compound of this invention is denoted deuterium, suchcompound has an isotopic enrichment factor for each designated deuteriumatom of at least 3500 (52.5% deuterium incorporation at each designateddeuterium atom), at least 4000 (60% deuterium incorporation), at least4500 (67.5% deuterium incorporation), at least 5000 (75% deuteriumincorporation), at least 5500 (82.5% deuterium incorporation), at least6000 (90% deuterium incorporation), at least 6333.3 (95% deuteriumincorporation), at least 6466.7 (97% deuterium incorporation), at least6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuteriumincorporation).

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Compounds of the invention that contain groups capable of acting asdonors and/or acceptors for hydrogen bonds may be capable of formingco-crystals with suitable co-crystal formers. These co-crystals may beprepared from compounds of formula (I′), (I), (Ia′), (Ia) or (Ib) byknown co-crystal forming procedures. Such procedures include grinding,heating, co-subliming, co-melting, or contacting in solution compoundsof formula (I′), (I), (Ia′), (Ia) or (Ib) with the co-crystal formerunder crystallization conditions and isolating co-crystals therebyformed. Suitable co-crystal formers include those described in WO2004/078163. Hence the invention further provides co-crystals comprisinga compound of formula (I′), (I), (Ia), (Ia) or (Ib).

The invention also envisages the use of pro-drugs of the compounds ofthe invention that convert in vivo to the compounds of the invention. Apro-drug is an active or inactive compound that is modified chemicallythrough in vivo physiological action, such as hydrolysis, metabolism andthe like, into a compound of the invention following administration ofthe prodrug to a subject. The suitability and techniques involved inmaking and using pro-drugs are well known by those skilled in the art.Prodrugs can be conceptually divided into two non-exclusive categories,bioprecursor prodrugs and carrier prodrugs. See The Practice ofMedicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego,Calif., 2001).

Furthermore, the compounds of the invention, including their salts, canalso be obtained in the form of their hydrates, or include othersolvents used for their crystallization. The compounds of the inventionmay inherently or by design form solvates with pharmaceuticallyacceptable solvents (including water); therefore, it is intended thatthe invention embrace both solvated and unsolvated forms. The term“solvate” refers to a molecular complex of a compound of the invention(including pharmaceutically acceptable salts thereof) with one or moresolvent molecules. Such solvent molecules are those commonly used in thepharmaceutical art, which are known to be innocuous to the recipient,e.g., water, ethanol, and the like. The term “hydrate” refers to thecomplex where the solvent molecule is water. The compounds of theinvention, including salts, hydrates and solvates thereof, mayinherently or by design form polymorphs.

Various embodiments of the invention are described herein. It will berecognized that features specified in each embodiment may be combinedwith other specified features to provide further embodiments of thepresent invention.

The definition of the substituents applies to compounds of formula (I),(I′), (Ia), (Ia′) and (Ib) as applicable.

The definition of the substituents applies to the end-products as wellas to the corresponding intermediates.

Embodiment 1

A compound of formula (I′) in free form or in pharmaceuticallyacceptable salt form as described above.

Embodiment 2

A compound of formula (I) in free form or in pharmaceutically acceptablesalt form as described above.

Embodiment 3

A compound of formula (Ia′) in free form or in pharmaceuticallyacceptable salt form according to embodiment 1 as described above.

Embodiment 4

A compound of formula (Ia) in free form or in pharmaceuticallyacceptable salt form according to embodiment 2 as described above

Embodiment 5

A compound of formula (Ib) in free form or in pharmaceuticallyacceptable salt form according to embodiment 1 or 2 as described above.

Embodiment 6

A compound of formula (Ia) in free form or in pharmaceuticallyacceptable salt form according to embodiment 4, wherein

-   -   a) R₁ is a five- to six-membered monocyclic saturated or        unsaturated non-aromatic ring system, wherein said ring system        may contain from 1 to 4 hetero atoms selected from nitrogen,        oxygen and sulfur, and wherein said ring system may be        substituted once or more than once by R₆;        -   and        -   R₂ is C₂₋₆alkyl which may be substituted once or more than            once by R₇;        -   or R₂ is —X₁—R₈; —X₁— is —O—, —S— or —N(R₉)—; R₉ is hydrogen            or C₁₋₄alkyl; and R₈ is C₁₋₆alkyl which may be substituted            once or more than once by R₁₀;        -   or R₂ is a three- to five-membered monocyclic saturated or            unsaturated non-aromatic ring system, wherein said ring            system may contain from 1 to 4 hetero atoms selected from            nitrogen, oxygen and sulfur, and wherein said ring system            may be substituted once or more than once by R₁₁;            or    -   b) R₁ is

-   -   -   wherein the phenyl ring is attached via the bond marked with            an asterisk;        -   each R₁₂ independently is hydrogen, halogen, hydroxyl,            amino, cyano, nitro, C₁₋₄alkyl, C₁₋₄halogenalkyl,            C₁₋₄hydroxyalkyl, C₁₋₄alkoxy-C₁₋₄alkyl, amino-C₁₋₄alkyl,            C₁₋₄alkyl-amino-C₁₋₄alkyl, di(C₁₋₄alkyl)-amino-C₁₋₄alkyl,            C₁₋₄alkoxy, C₁₋₄halogenalkoxy, C₁₋₄alkylamino or            di(C₁₋₄alkyl)amino; or C₃₋₆cycloalkyl, wherein one carbon            atom may be replaced by an oxygen atom, wherein the            C₃₋₆cycloalkyl may be attached directly or via a            C₁₋₂alkylene, and wherein the C₃₋₆cycloalkyl may be            substituted once or more than once by halogen;        -   and        -   R₂ is C₂₋₇alkyl which may be substituted once or more than            once by R₁₃;        -   or R₂ is —X₂—R₁₄; —X₂— is —O—, —S— or —N(R₁₅)—; R₁₅ is            hydrogen or C₁₋₄alkyl; and R₁₄ is C₁₋₆alkyl which may be            substituted once or more than once by R₁₆;        -   or R₂ is a three- to five-membered monocyclic saturated or            unsaturated non-aromatic ring system, wherein said ring            system may contain from 1 to 4 hetero atoms selected from            nitrogen, oxygen and sulfur, and wherein said ring system            may be substituted once or more than once by R₁₇;            or

    -   c) R₁ is a ring selected from pyrazolyl, thiophenyl or        pyridin-2-yl, which ring may be substituted by C₁₋₃alkyl;

    -   and

    -   R₂ is C₂₋₇alkyl which may be substituted once or more than once        by R₁₃;

    -   or R₂ is —X₂—R₁₄; —X₂— is —O—, —S— or —N(R₁₅)—; R₁₅ is hydrogen        or C₁₋₄alkyl; and R₁₄ is C₁₋₆alkyl which may be substituted once        or more than once by R₁₆;

    -   or R₂ is a three- to five-membered monocyclic saturated or        unsaturated non-aromatic ring system, wherein said ring system        may contain from 1 to 4 hetero atoms selected from nitrogen,        oxygen and sulfur, and wherein said ring system may be        substituted once or more than once by R₁₇;

    -   R₃ is hydrogen or —CH₂R₁₈;

    -   R₁₈ is hydrogen, C₁₋₄alkyl, C₂₋₆alkenyl, C₃₋₆cycloalkyl,        C₁₋₃alkoxyC₁₋₃alkyl, hydroxyC₁₋₃alkyl, or aminoC₁₋₃alkyl;

    -   and

    -   R₂₁ is hydrogen, halogen, hydroxyl, amino, cyano, C₁₋₄alkyl,        C₁₋₄halogenalkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkylamino-C₁₋₄alkyl,        di(C₁₋₄alkoxy, C₁₋₄halogenalkoxy, C₁₋₄alkylamino or        di(C₁₋₄alkyl)amino;

    -   or a three- to seven-membered monocyclic aromatic, saturated or        unsaturated non-aromatic ring system, wherein said ring system        may contain from 1 to 4 hetero atoms selected from nitrogen,        oxygen and sulfur, wherein said ring system may be attached        directly or via a C₁₋₂alkylene, and wherein said ring system may        be substituted once or more than once by R₂₃;

    -   or

    -   R₃ and R₂₁ taken together are —CH₂—CH₂—;

    -   R₂₂ is hydrogen, halogen, hydroxyl, cyano, C₁₋₄alkyl,        C₂₋₄alkenyl, C₂₋₄alkinyl or C₁₋₄alkoxy; or C₃₋₄cycloalkyl,        wherein one carbon atom may be replaced by an oxygen atom,        wherein the C₃₋₄cycloalkyl may be attached directly or via a        C₁₋₂alkylene;

    -   R₆, R₁₁, R₁₇ and R₂₃ each independently is halogen, hydroxyl,        amino, cyano, nitro, C₁₋₄alkyl, C₁₋₄halogenalkyl,        C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄halogenalkoxy, C₁₋₄alkylamino        or di(C₁₋₄alkyl)amino;

    -   or C₃₋₆cycloalkyl, wherein one carbon atom may be replaced by an        oxygen atom, wherein the C₃₋₆cycloalkyl may be attached directly        or via a C₁₋₂alkylene, and wherein the C₃₋₆cycloalkyl may be        substituted once or more than once by halogen;

    -   or two R₆, R₁₁, R₁₇ or R₂₃ at the same ring atom together are        oxo;

    -   or two R₆, R₁₁, R₁₇ or R₂₃ at the same ring carbon atom together        with said carbon atom form a C₃₋₆cycloalkyl;

    -   R₇, R₁₀, R₁₃ and R₁₆ each independently is halogen, hydroxyl,        amino, cyano, nitro, C₁₋₄alkoxy, C₁₋₄halogenalkoxy,        C₁₋₄alkylamino or di(C₁₋₄alkyl)amino;

    -   or C₃₋₆cycloalkyl, wherein one carbon atom may be replaced by an        oxygen atom, wherein the C₃₋₆cycloalkyl may be attached directly        or via a C₁₋₂alkylene, and wherein the C₃₋₆cycloalkyl may be        substituted once or more than once by halogen;

    -   or two R₇, R₁₀, R₁₃ or R₁₆ at the same carbon atom together are        oxo;

    -   or two R₇, R₁₀, R₁₃ or R₁₆ at the same carbon atom together with        said carbon atom form a C₃₋₆cycloalkyl.

Embodiment 7

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to any of embodiments 1to 5, wherein R₁ is

wherein the phenyl ring is attached via the bond marked with anasterisk;each R₁₂ independently is hydrogen, halogen, hydroxyl, amino, cyano,nitro, C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄hydroxyalkyl,C₁₋₄alkoxy-C₁₋₄alkyl, amino-C₁₋₄alkyl, C₁₋₄alkyl-amino-C₁₋₄alkyl,di(C₁₋₄)alkyl)-amino-C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄halogenalkoxy,C₁₋₄alkylamino or di(C₁₋₄alkyl)amino; or C₃₋₆cycloalkyl, wherein onecarbon atom may be replaced by an oxygen atom, wherein theC₃₋₆cycloalkyl may be attached directly or via a C₁₋₂alkylene, andwherein the C₃₋₆cycloalkyl may be substituted once or more than once byhalogen;andR₂ is C₂₋₇alkyl which may be substituted once or more than once by R₁₃;or R₂ is —X₂—R₁₄; —X₂— is —O—, —S— or —N(R₁₅)—; R₁₅ is hydrogen orC₁₋₄alkyl; and R₁₄ is C₁₋₆alkyl which may be substituted once or morethan once by R₁₆;or R₂ is a three- to five-membered monocyclic saturated or unsaturatednon-aromatic ring system, wherein said ring system may contain from 1 to4 hetero atoms selected from nitrogen, oxygen and sulfur, and whereinsaid ring system may be substituted once or more than once by R₁₇.

Embodiment 8

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to embodiment 7, whereineach R₁₂ independently is hydrogen, halogen, hydroxyl, amino, cyano,nitro, C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄alkoxy; or C₃₋₆cycloalkyl.

Embodiment 9

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to embodiment 8, whereineach R₁₂ is hydrogen.

Embodiment 10

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to any of embodiments 1to 6, wherein R₁ is a five- to six-membered monocyclic saturated orunsaturated non-aromatic ring system, wherein said ring system maycontain from 1 to 4 hetero atoms selected from nitrogen, oxygen andsulfur, and wherein said ring system may be substituted once or morethan once by R₆;

and

R₂ is C₂₋₆alkyl which may be substituted once or more than once by R₇;

or R₂ is —X₁— is —O—, —S— or —N(R₉)—; R₉ is hydrogen or C₁₋₄alkyl; andR₈ is C₁₋₆alkyl which may be substituted once or more than once by R₁₀;

or R₂ is a three- to five-membered monocyclic saturated or unsaturatednon-aromatic ring system, wherein said ring system may contain from 1 to4 hetero atoms selected from nitrogen, oxygen and sulfur, and whereinsaid ring system may be substituted once or more than once by R₁₁.

Embodiment 11

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to embodiment 10,wherein each R₆ independently is halogen, hydroxyl, amino, cyano, nitro,C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄alkoxy or C₃₋₆cycloalkyl.

Embodiment 12

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to any of embodiments 1to 6, wherein R₁ is pyrazolyl.

Embodiment 13

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to embodiment 12 whereinR₁ is a pyrazol-3-yl.

Embodiment 14

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to embodiment 12 or 13wherein R₁ is substituted with methyl.

Embodiment 15

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) according toembodiment 12 in free form or in pharmaceutically acceptable salt formwherein R₁ is a pyrazol-5-yl.

Embodiment 16

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to embodiment 15,wherein R₁ is a pyrazol-5-yl which is unsubstituted.

Embodiment 17

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to any of embodiments 1to 6, wherein R₁ is thiophenyl.

Embodiment 18

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to embodiment 17,wherein R₁ is thiophen-3-yl.

Embodiment 19

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to any of embodiments 1to 6, wherein R₁ is pyridin-2-yl.

Embodiment 20

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to any of embodiments 1to 19, wherein R₂ is C₂₋₆alkyl.

Embodiment 21

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to embodiment 20,wherein R₂ is n-propyl.

Embodiment 22

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to embodiment 20,wherein R₂ is isopropyl.

Embodiment 23

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to any of embodiments 1to 19, wherein R₂ is —X₁—R₈; is —O— or —S—; and R₈ is C₁₋₆alkyl.

Embodiment 24

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to any of embodiments 1to 19, wherein, R₂ is —X₁—R₈; is N(R₉)—; R₉ is C₁₋₄alkyl; and R₈ isC₁₋₆alkyl.

Embodiment 25

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to any of embodiments 1to 19, wherein R₂ is a three- to five-membered monocyclic saturated orunsaturated non-aromatic ring system, wherein said ring system maycontain from 1 to 4 hetero atoms selected from nitrogen, oxygen andsulfur, and wherein said ring system may be substituted once or morethan once by R₁₁; each R₁₁ independently is halogen, hydroxyl, amino,cyano, nitro, C₁₋₄alkyl, C₁₋₄alkoxy or C₃₋₆cycloalkyl.

Embodiment 26

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to embodiment 25,wherein R₂ is cyclopropyl.

Embodiment 27

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to embodiment 25,wherein R₂ is cyclobutyl.

Embodiment 28

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to embodiment 25,wherein R₂ is cyclopentyl.

Embodiment 29

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to any of embodiments 1to 28, wherein R₃ is hydrogen or —CH₂R₁₈, R₁₈ is hydrogen, C₁₋₄alkyl,C₂₋₆alkenyl or C₃₋₆cycloalkyl.

Embodiment 30

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to embodiment 29,wherein R₃ is hydrogen.

Embodiment 31

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to embodiment 29,wherein R₃ is CH₂R₁₅ and R₁₈ is hydrogen.

Embodiment 32

A compound of formula (I), (I′), (Ia), or (Ia′) in free form or inpharmaceutically acceptable salt form according to any of embodiments 1to 28 wherein R₃ and R₂₁ taken together are —CH₂—CH₂—.

Embodiment 33

A compound of formula (I), (I′), (Ia) or (Ia′) in free form or inpharmaceutically acceptable salt form according to any of embodiments 1to 28 wherein R₂₁ is hydrogen.

Embodiment 34

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to any of embodiments 1to 33, wherein R₂₂ is hydrogen, halogen, hydroxyl, cyano, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkinyl or C₁₋₄alkoxy; or C₃₋₄cycloalkyl, wherein onecarbon atom may be replaced by an oxygen atom, wherein theC₃₋₄cycloalkyl may be attached directly or via a C₁₋₂alkylene.

Embodiment 35

A compound of formula (I), (I′), (Ia), (Ia′) or (Ib) in free form or inpharmaceutically acceptable salt form according to embodiment 34,wherein R₂₂ is hydrogen.

Embodiment 36

A compound of formula (I), (I′) or (Ib) in free form or inpharmaceutically acceptable salt form according to any of embodiments 1to 28, wherein R₄ and R₅ together with the bond to which they areattached form a 5- to 7-membered monocyclic non-aromatic carbocyclicring which may be substituted once or more than once by R₁₉; R₁₉ isselected from halogen or C₁-C₃alkyl.

Embodiment 37

A compound of formula (I), (I′) or (Ib) in free form or inpharmaceutically acceptable salt form according to embodiment 36,wherein R₄ and R₅ together with the bond to which they are attached forma cyclopentyl ring.

Embodiment 38

A compound of formula (I), (I′) or (Ib) in free form or inpharmaceutically acceptable salt form according to embodiment 36,wherein R₄ and R₅ together with the bond to which they are attached forma cyclohexyl ring.

Embodiment 39

A compound of formula (I), (I′) or (Ib) in free form or inpharmaceutically acceptable salt form according to embodiment 38 whereinR₄ and R₅ together with the bond to which they are attached form acyclohexyl ring substituted once with C₁-C₃alkyl.

Embodiment 40

A compound of formula (I), (I′) or (Ib) in free form or inpharmaceutically acceptable salt form according to embodiment 36,wherein R₄ and R₅ together with the bond to which they are attached forma cycloheptyl ring.

Embodiment 41

A compound of formula (I), (I′) or (Ib) in free form or inpharmaceutically acceptable salt form according to any of embodiments 1to 28, wherein R₄ and R₅ together with the bond to which they areattached form a thiophene ring.

Embodiment 42

A compound of formula (I), (I′) or (Ib) in free form or inpharmaceutically acceptable salt form according to embodiment 41,wherein R₄ and R₅ together with the bond to which they are attached forma thiophene ring attached to the rest of the molecule to give athieno[2,3-b][1,6]naphthyridinedione compound.

Embodiment 43

A compound of formula (I), (I′) or (Ib) in free form or inpharmaceutically acceptable salt form according to embodiment 41,wherein R₄ and R₅ together with the bond to which they are attached forma thiophene ring attached to the rest of the molecule to give athieno[3,2-b][1,6]naphthyridinedione compound.

Embodiment 44

A compound of formula (I), (I′) or (Ib) in free form or inpharmaceutically acceptable salt form according to embodiment 41,wherein R₄ and R₅ together with the bond to which they are attached forma thiophene ring attached to the rest of the molecule to give athieno[3,4-b][1,6]naphthyridinedione compound.

Embodiment 45

A compound of formula (I), (I′) or (Ib) in free form or inpharmaceutically acceptable salt form according to any of embodiments 41to 44, wherein R₄ and R₅ together with the bond to which they areattached form a thiophene ring substituted once with C₁-C₃alkyl.

Embodiment 46

A compound of formula (I), (I′) or (Ib) in free form or inpharmaceutically acceptable salt form according to any of embodiments 41to 44, wherein R₄ and R₅ together with the bond to which they areattached form an unsubstituted thiophene ring.

Embodiment 47

A compound of formula (I), (I′) or (Ib) in free form or inpharmaceutically acceptable salt form according to any of embodiments 1to 28, wherein R₄ is hydrogen.

Embodiment 48

A compound of formula (I), (I′) or (Ib) in free form or inpharmaceutically acceptable salt form according to any of embodiments 1to 28, wherein R₄ is methyl.

Embodiment 49

A compound of formula (I), (I′) or (Ib) in free form or inpharmaceutically acceptable salt form according to any of embodiments 47or 48, wherein R₅ is hydrogen.

Embodiment 50

A compound of formula (I), (I′) or (Ib) in free form or inpharmaceutically acceptable salt form according to any of embodiments 47or 48, wherein R₅ is methyl.

Embodiment 51

A compound of formula (I′) in free form or in pharmaceuticallyacceptable salt form according to embodiment 1, which is selected from

-   3-cyclobutyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   3-cyclobutyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   3-isopropyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   8-fluoro-3-isopropyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   8-fluoro-3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   8-chloro-3-isopropyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   8-chloro-3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   3-isopropyl-8-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   3-isopropyl-5,8-dimethyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   9-isopropyl-8-phenyl-1H-indolo[1,7-ab][1,6]naphthyridine-6,7(2H,8H)-dione;-   7-isopropyl-6-phenylthieno[2,3-b][1,6]naphthyridine-4,5(6H,9H)-dione;-   7-isopropyl-9-methyl-6-phenylthieno[2,3-b][1,6]naphthyridine-4,5(6H,9H)-dione;-   7-isopropyl-2-methyl-6-phenylthieno[2,3-b][1,6]naphthyridine-4,5(6H,9H)-dione;-   7-isopropyl-2,9-dimethyl-6-phenylthieno[2,3-b][1,6]naphthyridine-4,5(6H,9H)-dione;-   6-isopropyl-7-phenylthieno[3,2-b][1,6]naphthyridine-8,9(4H,7H)-dione;-   6-isopropyl-4-methyl-7-phenylthieno[3,2-b][1,6]naphthyridine-8,9(4H,7H)-dione;-   6-isopropyl-2-methyl-7-phenylthieno[3,2-b][1,6]naphthyridine-8,9(4H,7H)-dione;-   6-isopropyl-2,4-dimethyl-7-phenylthieno[3,2-b][1,6]naphthyridine-8,9(4H,7H)-dione;-   6-isopropyl-3-methyl-7-phenylthieno[3,2-b][1,6]naphthyridine-8,9(4H,7H)-dione;-   6-isopropyl-3,4-dimethyl-7-phenylthieno[3,2-b][1,6]naphthyridine-8,9(4H,7H)-dione;-   3-isopropyl-2-phenyl-6,7,8,9-tetrahydrobenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   3-isopropyl-2-phenyl-5,6,7,8-tetrahydro-1H-cyclopenta[b][1,6]naphthyridine-1,9(2H)-dione;-   3-cyclobutyl-5-methyl-2-phenyl-5,6,7,8-tetrahydro-1H-cyclopenta[b][1,6]naphthyridine-1,9(2H)-dione;-   7-cyclobutyl-1,2,3-trimethyl-6-phenyl-1,6-naphthyridine-4,5(1H,6H)-dione;-   3-cyclobutyl-2-phenyl-5,6,7,8-tetrahydro-1H-cyclopenta[b][1,6]naphthyridine-1,9(2H)-dione;-   7-cyclobutyl-2,3-dimethyl-6-phenyl-1,6-naphthyridine-4,5(1H,6H)-dione;-   3-cyclobutyl-5-methyl-2-phenyl-6,7,8,9-tetrahydrobenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   7-cyclobutyl-9-methyl-6-phenylthieno[2,3-b][1,6]naphthyridine-4,5(6H,9H)-dione;-   3-cyclobutyl-2-phenyl-6,7,8,9-tetrahydrobenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   7-cyclobutyl-2,9-dimethyl-6-phenylthieno[2,3-b][1,6]naphthyridine-4,5(6H,9H)-dione;-   7-cyclobutyl-6-phenylthieno[2,3-b][1,6]naphthyridine-4,5(6H,9H)-dione;-   7-cyclobutyl-2-methyl-6-phenylthieno[2,3-b][1,6]naphthyridine-4,5(6H,9H)-dione;-   6-cyclobutyl-4-methyl-7-phenylthieno[3,2-b][1,6]naphthyridine-8,9(4H,7H)-dione;-   6-cyclobutyl-7-phenylthieno[3,2-b][1,6]naphthyridine-8,9(4H,7H)-dione;-   6-cyclobutyl-2,4-dimethyl-7-phenylthieno[3,2-b][1,6]naphthyridine-8,9(4H,7H)-dione;-   6-cyclobutyl-2-methyl-7-phenylthieno[3,2-b][1,6]naphthyridine-8,9(4H,7H)-dione;-   3-cyclobutyl-5,8-dimethyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   3-cyclobutyl-8-fluoro-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   8-chloro-3-cyclobutyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   3-cyclobutyl-8-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   8-chloro-3-cyclobutyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   3-isopropyl-6-methoxy-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   3-cyclobutyl-8-fluoro-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   9-cyclobutyl-8-phenyl-1H-indolo[1,7-ab][1,6]naphthyridine-6,7(2H,8H)-dione;-   3-cyclobutyl-6-methoxy-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   3-isopropyl-6-methoxy-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   3-cyclobutyl-6-methoxy-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   3-isopropyl-8-methoxy-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   3-isopropyl-8-methoxy-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   8-hydroxy-3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   6-hydroxy-3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   3-cyclobutyl-2-cyclopentylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   3-cyclobutyl-2-cyclopentyl-5-methylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   2-cyclopentyl-3-isopropylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   2-cyclopentyl-3-isopropyl-5-methylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   3-cyclobutyl-2-(pyridin-2-yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   3-cyclobutyl-5-methyl-2-(pyridin-2-yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   3-cyclobutyl-2-(pyrrolidin-1-yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   3-cyclobutyl-5-methyl-2-(pyrrolidin-1-yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   4-chloro-3-isopropyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;-   4-chloro-3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;    and-   4-bromo-3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione.

Compounds of the formula (I), (I′), (Ia), (Ia′) or (Ib) can be preparedby conventional processes, e.g. as described in the Examples, whichprocesses are further aspects of the invention. Furthermore, compoundsof formula (I), (I′), (Ia), (Ia′) or (Ib) or their precursors may beobtainable from compounds which are described in the Examples, e.g. byreduction, oxidation and/or other functionalization of resultingcompounds and/or by cleavage of any protecting group(s) optionallypresent, and of recovering the so obtainable compound of the formula(I), (I′), (Ia), (Ia′) or (Ib) or the intended precursor. The reactionscan be effected according to conventional methods, for example asdescribed in the Examples. The work-up of the reaction mixtures and thepurification of the compounds thus obtainable may be carried out inaccordance with known procedures. Acid addition salts may be producedfrom the free bases in known manner, and vice-versa. Starting materials,e.g. starting materials as described in the Examples, may be known orprepared according to conventional procedures starting from knowncompounds.

The invention also contemplates that compounds of formula (I), (I′),(Ia), (Ia′) or (Ib) may be formed by in vivo biotransformation frompro-drugs.

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of the invention and a pharmaceutically acceptablecarrier. The pharmaceutical composition can be formulated for particularroutes of administration such as oral administration, parenteraladministration, and rectal administration, etc. In addition, thepharmaceutical compositions of the invention can be made up in a solidform including capsules, tablets, pills, granules, powders orsuppositories, or in a liquid form including solutions, suspensions oremulsions. The pharmaceutical compositions can be subjected toconventional pharmaceutical operations such as sterilization and/or cancontain conventional inert diluents, lubricating agents, or bufferingagents, as well as adjuvants, such as preservatives, stabilizers,wetting agents, emulsifers and buffers etc.

Typically, the pharmaceutical compositions are tablets and gelatincapsules comprising the active ingredient together with

-   -   a) diluents, e.g., lactose, dextrose, sucrose, mannitol,        sorbitol, cellulose and/or glycine;    -   b) lubricants, e.g., silica, talcum, stearic acid, its magnesium        or calcium salt and/or polyethyleneglycol; for tablets also    -   c) binders, e.g., magnesium aluminum silicate, starch paste,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and/or polyvinylpyrrolidone; if desired    -   d) disintegrants, e.g., starches, agar, alginic acid or its        sodium salt, or effervescent mixtures; and/or    -   e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets contain the active ingredient in admixture withnontoxic pharmaceutically acceptable excipients which are suitable forthe manufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, or contain about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with carrier. Carriers includeabsorbable pharmacologically acceptable solvents to assist passagethrough the skin of the host. For example, transdermal devices are inthe form of a bandage comprising a backing member, a reservoircontaining the compound optionally with carriers, optionally a ratecontrolling barrier to deliver the compound of the skin of the host at acontrolled and predetermined rate over a prolonged period of time, andmeans to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. They arethus particularly suited for use in topical, including cosmetic,formulations well-known in the art. Such may contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

As used herein a topical application may also pertain to an inhalationor to an intranasal application. They are conveniently delivered in theform of a dry powder (either alone, as a mixture, for example a dryblend with lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurised container, pump, spray, atomizer ornebuliser, with or without the use of a suitable propellant.

The invention further provides anhydrous pharmaceutical compositions anddosage forms comprising the compounds of the invention as activeingredients, since water may facilitate the degradation of certaincompounds.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. An anhydrous pharmaceuticalcomposition may be prepared and stored such that its anhydrous nature ismaintained. Accordingly, anhydrous compositions are preferably packagedusing materials known to prevent exposure to water such that they can beincluded in suitable formulary kits. Examples of suitable packaginginclude, but are not limited to, hermetically sealed foils, plastics,unit dose containers (e.g., vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the invention as an active ingredient will decompose. Suchagents, which are referred to herein as “stabilizers,” include, but arenot limited to, antioxidants such as ascorbic acid, pH buffers, or saltbuffers, etc.

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drugs, drug stabilizers, binders, excipients,disintegration agents, lubricants, sweetening agents, flavoring agents,dyes, such like materials and combinations thereof, as would be known toone of ordinary skill in the art (see, for example, Remington'sPharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp.1289-1329). Except insofar as any conventional carrier is incompatiblewith the active ingredient, its use in the therapeutic or pharmaceuticalcompositions is contemplated.

The compounds of formula I or pharmaceutical acceptable salts thereofexhibit valuable pharmacological properties and are therefore useful aspharmaceuticals.

Furthermore, compounds of formula (I), (I′), (Ia), (Ia′) or (Ib) may beuseful for research on diseases caused by nonsense mutations, e.g. astool compounds.

In particular, compounds of formula (I), (I′), (Ia), (Ia′) or (Ib) I actas nonsense mutation suppressors on frequent PTCs, e.g. on Y122X in themRNA of the cystic fibrosis conductance regulator protein (CFTR). Thiscan be determined in vitro, for example, using cell lines expressingGFP-CFTR-Y122X-Renilla constructs as described herein.

The compounds of the invention may be therefore useful in theprevention, treatment or delay of progression of diseases caused bynonsense mutations

The term “disease caused by nonsense mutation” is known in the field. Itrelates to a disease being present in patients carrying a nonsensemutation in a disease-relevant gene wherein the nonsense mutation causesa partial/total lack of protein which then causes the pathology of thedisease.

In one embodiment, the disease is selected from hemophilia A, hemophiliaB, cystic fibrosis, mucopolysaccharidosis I, Duchenne Muscle Dystrophy,Becker Muscle Dystrophy, loss of APC caused cancer and loss of p53caused cancer.

For the above-mentioned indications (the conditions and disorders) theappropriate dosage will vary depending upon, for example, the compoundemployed, the host, the mode of administration and the nature andseverity of the condition being treated. However, in general,satisfactory results in animals are indicated to be obtained at a dailydosage of from about 0.01 to about 100 mg/kg body weight, preferablyfrom about 0.1 to about 10 mg/kg body weight, e.g. 1 mg/kg. In largermammals, for example humans, an indicated daily dosage is in the rangefrom about 0.1 to about 1000 mg, preferably from about 1 to about 400mg, most preferably from about 10 to about 100 mg of the compound of theinvention conveniently administered, for example, in divided doses up tofour times a day.

For use according to the invention, a compound of the invention may beadministered as single active agent or in combination with other activeagents, in any usual manner, e.g. orally, for example in the form oftablets or capsules, or parenterally, for example in the form ofinjection solutions or suspensions. A combination comprising a compoundof the invention and another active agent will be referred to as“combination of the invention”.

A compound of the invention, may be combined with a readthroughactivator, e.g. negamycin, RT13, RT14, ataluren or an aminoglycosidereadthrough activator, e.g. paromomycin, amikacin, G418, NB30, NB54 orNB84.

A compound of the invention, may be combined with a nonsense-mediatedmRNA decay inhibitor, e.g. NMDI-1.

Negamycin, RT13, RT14, ataluren, aminoglycoside readthrough activatorsand NMDI-1 are described e.g. in Keeling et al, WIREs RNA, 2011, 2,837-852.

The compounds of the invention may be useful for the prevention ofdiseases caused by nonsense mutations.

The compounds of the invention may be useful for the treatment ofdiseases caused by nonsense mutations.

The compounds of the invention may be useful for the delay ofprogression of diseases caused by nonsense mutations.

In another embodiment, the invention provides a method of treating adisease caused by a nonsense mutation comprising administration of atherapeutically effective amount of a compound of formula (I), (I′),(Ia), (Ia′) or (Ib) or a pharmaceutically acceptable salt thereof. In afurther embodiment, the invention provides a method of treating adisease caused by a nonsense mutation comprising administration of atherapeutically effective amount of a compound of formula (I), (I′),(Ia), (Ia′) or (Ib) or a pharmaceutically acceptable salt thereof,wherein the disease is selected from the afore-mentioned list, suitablyhemophilia A, hemophilia B, cystic fibrosis and mucopolysaccharidosis I(Hurler syndrome).

The term “a therapeutically effective amount” of a compound of theinvention refers to an amount of the compound of the invention that willelicit the biological or medical response of a subject, for example,ameliorate symptoms, alleviate conditions, slow or delay diseaseprogression, or prevent a disease, etc. In one non-limiting embodiment,the term “a therapeutically effective amount” refers to the amount ofthe compound of the invention that, when administered to a subject, iseffective to at least partially alleviating, inhibiting, preventingand/or ameliorating a disease caused by nonsense mutations. In anothernon-limiting embodiment, the term “a therapeutically effective amount”refers to the amount of the compound of the invention that, whenadministered to a cell, or a tissue, or a non-cellular biologicalmaterial, or a medium, is effective to at least partially suppress theeffect of nonsense mutations.

As used herein, the term “subject” refers to an animal. Preferably, theanimal is a mammal. A subject also refers to for example, primates(e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats,mice, fish, birds and the like. In a preferred embodiment, the subjectis a human.

As used herein, the term “inhibition” or “inhibiting” refers to thereduction or suppression of a given condition, symptom, or disorder, ordisease, or a significant decrease in the baseline activity of abiological activity or process.

As used herein, the term “treating” or “treatment” of any disease ordisorder refers in one embodiment, to ameliorating the disease ordisorder (i.e., slowing or arresting or reducing the development of thedisease or at least one of the clinical symptoms thereof). In anotherembodiment “treating” or “treatment” refers to alleviating orameliorating at least one physical parameter including those which maynot be discernible by the patient. In yet another embodiment, “treating”or “treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers topreventing or delaying the onset or development or progression of thedisease or disorder.

The pharmaceutical composition or combination of the invention can be inunit dosage of about 1-1000 mg of active ingredient(s) for a subject ofabout 50-70 kg, or about 1-500 mg or about 1-250 mg or about 1-150 mg orabout 0.5-100 mg, or about 1-50 mg of active ingredients. Thetherapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of theinvention can be applied in vitro in the form of solutions, e.g.,preferably aqueous solutions, and in vivo either enterally,parenterally, advantageously intravenously, e.g., as a suspension or inaqueous solution. The dosage in vitro may range between about 10⁻³ molarand 10⁻⁹ molar concentrations. A therapeutically effective amount invivo may range depending on the route of administration, between about0.1-500 mg/kg, or between about 1-100 mg/kg.

The activity of a compound of the invention can be assessed by in vitro& in vivo methods described herein.

The compound of the invention may be administered either simultaneouslywith, or before or after, at least one other therapeutic agent. Thecompound of the invention may be administered separately, by the same ordifferent route of administration, or together in the samepharmaceutical composition.

The following Examples illustrate the invention, but do not limit it.

EXPERIMENTAL PART

Abbreviations:

-   NMP 1-methylpyrrolidin-2-one-   HOAt 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol-   HATU    2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium    hexafluorophosphate(V)-   DMF dimetylformamide-   DCM dichloromethane-   ACN acetonitrile-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TBME t-Butylmethylether-   r.t. room temperature-   SFC superitical fluid chromatography-   RP reverse phase-   HPLC high pressure liquid chromatography-   DIEA N,N-Diisopropylethylamine-   rac-BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl racemate-   dba dibenzylideneacetone-   DMA dimethylacetamide    LC-MS Method:

Waters Acquity UPLC-SQD system; mobile phase: A: water (0.05% formicacid) B: methanol (0.04% formic acid); gradient: from 2% B to 8% B in0.1 min, from 8% B to 98% B in 0.5 min, 98% B for 0.1 min; flow rate 1mL/min; column Waters Acquity UPLC BEH C18, 30×2.1 mm, 1.7 mM; oventemperature 60° C.

NMR Device:

Bruker Avance 400 MHz Ultrashield and Avance 600 MHz

Examples Example 1.1:3-Cyclobutyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione

a) 3-(Cyclobutanecarbonyl)-6-cyclobutyl-4-hydroxy-2H-pyran-2-one

Under argon 64.1 g cabonyldiimidazol (396 mmol) was added to 31.5 mLcyclobutanecarboxylic acid (330 mmol) in 300 mL THF within 10 minutes atr.t. After 25 minutes 226 mL DCM, 77 g potassium3-methoxy-3-oxopropanoate (494 mmol) and 37.7 g magnesium chloride (396mmol) were added subsequently, heated up to 56° C. within 2.5 hours, andstirred for another 3.5 hours. The resulting suspension was cooled tor.t., 600 mL 2N aqueous hydrochloric acid was added to reach pH 2,another 800 mL water was added and the resulting biphasic solution wasseparated. The aqueous phase was extracted twice with 250 mL DCM, thecombined organic phases were washed with half concentrated aqueoussodium chloride solution, dried over sodium sulfate, filtered andevaporated. The resulting methyl 3-cyclobutyl-3-oxopropanoate (59 g,used for the next step without purification) was dissolved in 10 mLmethanol, 378 mL 2M aqueous sodium hydroxide solution was added and themixture was stirred for one hour. 100 mL TBME was added, the aqueousphase twice extracted with 50 mL TBME, combined aqueous phases filteredand cooled to 5° C. To that solution 65.1 mL concentrated aqueoushydrochloric acid was added to reach pH <1. 167 g solid sodium chloridewas added and the mixture was four times extracted with 100 mL ethylacetate, organic phases washed with water, dried over sodium sulfate,and evaporated to yield 3-cyclobutyl-3-oxopropanoic acid (43 g, used forthe next step without purification) as a slightly yellow oil. This oilwas dissolved in 508 mL THF and 53.1 g carbonyldiimidazol (328 mmol)were added carefully and stirred for 6 hours. To the resulting solution50 mL water was added, the THF evaporated under reduced pressure, 200 mLDCM added and washed with 400 mL 2M aqueous hydrochloric acid, 200 mL0.5M aqueous hydrochloric acid, 200 mL water. Aqueous phases wereextracted with 100 mL DCM and combined organic phases were dried oversodium sulfate, filtered and evaporated. The suiting orange oil waspurified by liquid chromatography over silica gel with DCM/methanol aseluent. Target fractions were combined and evaporated to yield 22 g3-(cyclobutanecarbonyl)-6-cyclobutyl-4-hydroxy-2H-pyran-2-one (89 mmol,53%) as a slowly crystallizing oil.

ESI-MS [M+H]⁺ 249.2

¹H-NMR (400 MHz, CDCl₃): δ (ppm)=16.91 (s, 1H), 5.94 (s, 1H), 4.36-4.26(m, 1H), 3.35 (quint, 1H, J=8.6 Hz), 2.39-2.26 (m, 8H), 2.13-2.00 (m,2H), 1.99-1.81 (m, 2H).

b) 6-Cyclobutyl-4-hydroxy-2H-pyran-2-one

To 21.9 g 3-(cyclobutanecarbonyl)-6-cyclobutyl-4-hydroxy-2H-pyran-2-one(88 mmol) 65.7 mL concentrated sulfuric acid (88 mmol) was added and themixture was heated to 105° C. for 20 minutes and then cooled to 0° C.The mixture was carefully poured on 600 g ice, diluted with water to 800mL volume and extracted three times with 200 mL ethyl acetate. Combinedorganic phases were washed with aqueous sodium chloride solution, driedover sodium sulfate, filtered, evaporated, and purified by liquidchromatography over silica gel with DCM/methanol as eluent. Targetfractions were combined and evaporated to yield 11.6 g6-cyclobutyl-4-hydroxy-2H-pyran-2-one (70 mmol, 79%) as an off-whitesolid.

ESI-MS [M+H]⁺ 167.1

¹H-NMR (400 MHz, d₆-DMSO): δ (ppm)=11.61 (s, 1H), 5.94 (d, 1H, J=2.1Hz), 5.22 (d, 1H, J=2.1), 3.36 (quint, 1H, J=8.6 Hz), 2.24-2.08 (m, 4H),2.04-1.90 (m, 1H), 1.87-1.75 (m, 1H).

c) 6-Cyclobutyl-4-hydroxy-1-phenylpyridin-2(1H)-one

To a suspension of 11.5 g 6-cyclobutyl-4-hydroxy-2H-pyran-2-one (69mmol) in 231 mL acetic acid and 462 mL water 6.33 mL aniline was addedand heated to 85° C. for 22 hours. the mixture was evaporated, twicetoluene added and evaporated, 50 mL toluene added and stirred at 50° C.The suspension was filtered, the solid washed with toluene anddiethylether, and dried to yield 8.5 g6-cyclobutyl-4-hydroxy-1-phenylpyridin-2(1H)-one (35 mmol, 51%) as awhite solid.

ESI-MS [M+H]⁺242.2

¹H-NMR (400 MHz, d₆-DMSO): δ (ppm)=10.59 (s, 1H), 7.50-7.39 (m, 3H),7.19-7.12 (m, 2H), 5.86-5.81 (m, 1H), 5.55 (d, 1H, J=2.4 Hz), 3.09-2.99(m, 1H), 1.96-1.84 (m, 2H), 1.67-1.50 (m, 4H).

d) 6-Cyclobutyl-2-oxo-1-phenyl-1,2-dihydropyridin-4-yltrifluoromethanesulfonate

Under argon 8.4 g 6-cyclobutyl-4-hydroxy-1-phenylpyridin-2(1H)-one (35mmol) was suspended in 168 mL DCM, cooled to −25° C., 3.94 mL pyridinewas added followed by the addition of a solution of 7.03 mLtrifluoromethane-sulfonic anhydride in 35 mL DCM within 15 minutes. Thesuspension was stirred for 40 minutes, poured on 250 mL ice/watermixture and vigorously stirred. The aqueous phase was separated, twiceextracted with 80 mL DCM, combined organic phases washed with water,dried over sodium sulfate, and evaporated to result in 13 g6-cyclobutyl-2-oxo-1-phenyl-1,2-dihydropyridin-4-yltrifluoromethanesulfonate (35 mmol, 100%) as a yellow oil thatcrystallized upon standing.

ESI-MS [M+H]⁺ 374.1

¹H-NMR (400 MHz, d₆-DMSO): δ (ppm)=7.58-7.44 (m, 3H), 7.34-7.26 (m, 2H),6.57-6.52 (m, 1H), 6.44-6.38 (m, 1H), 3.16 (quint, 1H, J=8.8 Hz),2.09-1.95 (m, 2H), 1.71-1.53 (m, 4H).

e) Methyl2-((6-cyclobutyl-2-oxo-1-phenyl-1,2-dihydropyridin-4-yl)amino)benzoate

Under argon to a suspension of 3 g6-cyclobutyl-2-oxo-1-phenyl-1,2-dihydropyridin-4-yltrifluoromethane-sulfonate (8.1 mmol), 1.26 mL methyl 2-aminobenzoate(9.7 mmol), and 3.7 g caesium carbonate (11.3 mmol) in 32 mL toluene 60mg rac-BINAP (0.1 mmol) and 44 mg Pd₂(dba)₃ (0.05 mmol) were added andheated to 85° C. for 16 hours. The suspension was cooled to r.t, dilutedwith 60 mL DCM, filtered over Hyflo, and the filtrate evaporated. Theresulting orange oil was purified by liquid chromatography over silicagel with DCM/methanol as eluent. Target fractions were combined andevaporated to yield 2.68 g methyl2-((6-cyclobutyl-2-oxo-1-phenyl-1,2-dihydropyridin-4-yl)amino)benzoate(7.2 mmol, 88%) as an orange oil that crystallized upon standing.

ESI-MS [M+H]⁺ 375.3

¹H-NMR (400 MHz, d₆-DMSO): δ (ppm)=9.06 (s, 1H), 7.94 (dd, 1H, J=7.9,1.6 Hz), 7.66-7.54 (m, 2H), 7.51-7.39 (m, 3H), 7.21-7.15 (m, 3H), 6.09(d, 1H, J=2.5 Hz), 5.79 (d, 1H, J=2.3 Hz), 3.87 (s, 3H), 3.11-3.03 (m,1H), 2.01-1.89 (m, 2H), 1.70-1.52 (m, 4H).

f) 3-Cyclobutyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione

To 2.6 g methyl2-((6-cyclobutyl-2-oxo-1-phenyl-1,2-dihydropyridin-4-yl)amino)benzoate(6.9 mmol) 38 g polyphoshoric acid was added and heated to 120° C. for40 minutes. To the mixture 43 g ice was added, diluted with 440 mL waterand 152 g potassium bicarbonate was slowly added to reach pH 7-8. 100 mLTBME and 200 mL methanol, followed by 200 mL water were added andthoroughly stirred for 30 minutes. The suspension was filtered, thesolid washed with water and TBME and dried to yield 1.7 g3-cyclobutyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione (5mmol, 72%) as an off-white solid.

ESI-MS [M+H]⁺ 343.2; LCMS Rt [min], meth. A: 0.60.

¹H-NMR (400 MHz, d₆-DMSO): δ (ppm)=11.79 (s, 1H), 8.10 (d, 1H, J=7.9),7.67 (t, 1H, J=7.6), 7.57-7.41 (m, 4H), 7.36-7.20 (m, 3H), 6.22 (s, 1H),3.20-3.06 (m, 1H), 2.06-1.90 (m, 2H), 1.74-1.56 (m, 4H).

Example 1.2:3-Cyclobutyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione

To a suspension of 1.65 g3-cyclobutyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione (4.8mmol) (example 1.1) in 50 mL DMF 4.7 g caesium carbonate (14.4 mmol) and0.9 mL methyliodide (14.4 mmol) were added and stirred for 2.5 hours atr.t. To the resulting suspension 100 mL water was slowly added, cooledto 10° C., stirred for 30 minutes, filtered, the solid washed with 20 mLDMF/water (1:2, v/v), 100 mL water and dried under vacuum at 60° C. toyield 1.4 g3-cyclobutyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione(4 mmol, 84%) as an off-white solid.

ESI-MS [M+H]⁺ 357.2; LCMS Rt [min], meth. A: 0.61.

¹H-NMR (400 MHz, d₆-DMSO): δ (ppm)=8.21 (dd, 1H, J=7.8, 1.8 Hz), 7.84(d, 1H, J=8.6 Hz), 7.81-7.73 (m, 1H), 7.58-7.46 (m, 3H), 7.38 (t, 1H,J=7.4 Hz), 7.28-7.23 (m, 2H), 6.43 (s, 1H), 3.92 (s, 3H), 3.22-3.12 (m,1H), 2.22-2.10 (m, 2H), 1.73-1.56 (m, 4H).

Example 1.3:3-isopropyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione

a) 4-hydroxy-6-isopropyl-1-phenylpyridin-2(1H)-one

To a solution of 3 g (19.5 mmol) 4-hydroxy-6-isopropyl-2H-pyran-2-one(CAS 220809-37-0, commercially available) in 120 mL water and 60 mLacetic acid 1.8 mL (19.5 mmol) anilin was added and stirred at 85° C.for 16.5 hours. The resulting mixture was evaporated and purified byliquid chromatography over silica gel with DCM/methanol as eluent.Target fractions were combined and evaporated to yield 1.5 g (6.4 mmol,33%) 4-hydroxy-6-isopropyl-1-phenylpyridin-2(1H)-one as a white solid

b) 6-isopropyl-2-oxo-1-phenyl-1,2-dihydropyridin-4-yltrifluoromethanesulfonate

To a suspension of 2.9 g (12.8 mmol) of4-hydroxy-6-isopropyl-1-phenylpyridin-2(1H)-one in 34 mL DCM 1.87 mL (23mmol) pyridine were added, the mixture was cooled to −25° C., a solutionof 2.7 mL (16 mmol) trifluoromethanesulfonic anhydride in 11.4 mL DCMwas dropwise over 10 minutes and stirred for another 45 minutes at −25°C. 40 mL and 80 mL water were added, the organic phase extracted with 80mL water and brine, the aqueous phases twice extracted with 80 mLethylacetate, combined organic phases dried over sodium sulfate andevaporated to yield 4.6 g (12.4 mmol, 97%)6-isopropyl-2-oxo-1-phenyl-1,2-dihydropyridin-4-yltrifluoromethanesulfonate as a yellow solid.

c) methyl2-((6-isopropyl-2-oxo-1-phenyl-1,2-dihydropyridin-4-yl)amino)benzoate

To a solution of 4.6 g (12.7 mmol)6-isopropyl-2-oxo-1-phenyl-1,2-dihydropyridin-4-yltrifluoromethane-sulfonate in 71 mL dioxane 1.8 mL (14 mmol) methyl2-aminobenzoate and 4.4. mL (25 mmol) DIEA were added. Then 0.63 g (1mmol) rac-BINAP and 0.46 g (0.5 mmol) Pd₂(dba)₃ were added and themixture was stirred at 90° C. for 21 hours. The mixture was cooled tor.t., evaporated, diluted with 300 mL ethylacetate and three timesextracted with water, the organic phase dried over sodium sulfate andevaporated. The resulting black oil was purified by liquidchromatography over silica gel with heptane/ethylacetate as eluent.Target fractions were combined and evaporated to yield 2.2 g (6.1 mmol,48%) methyl2-((6-isopropyl-2-oxo-1-phenyl-1,2-dihydropyridin-4-yl)amino)benzoate asa red oil.

d) 3-isopropyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione

2.2 g (6.1 mmol) methyl2-((6-isopropyl-2-oxo-1-phenyl-1,2-dihydropyridin-4-yl)amino)benzoatewere dissolved in 24 mL polyphosphoric acid and heated to 125° C. for 5hours. The reaction mixture was cooled to r.t., hydrolyzed by slowaddition of 500 mL water and adjusted to pH 8 by careful addition ofsolid potassium bicarbonate. The resulting suspension was extracted with80 mL DCM, the organic phase twice extracted with 80 mL water and brine,the combined aqueous phases twice with 80 mL DCM. Combined aqueousphases were filtered and the remaining solid dried under reducedpressure to yield 1.1 g (3.3 mmol, 55%)3-isopropyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione as a noff-white solid.

ESI-MS [M+H]⁺ 331.2; LCMS Rt [min], meth. A: 0.60.

¹H-NMR (400 MHz, d₆-DMSO): δ (ppm)=11.74 (s, 1H), 8.10 (dd, J=8.1, 1.5Hz, 1H), 7.67 (td, J=7.7, 7.1, 1.6 Hz, 1H), 7.60-7.43 (m, 4H), 7.35-7.26(m, 3H), 6.24 (s, 1H), 2.41 (sep, J=6.8 Hz, 1H), 1.10 (d, J=6.7 Hz, 6H).

Example 1.4:3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione

To a solution of 630 mg (1.9 mmol)3-isopropyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione in 34mL DMF 1.86 g caesium carbonate (5.7 mmol) and 0.81 g methyl iodide (5.7mmol) were added at stirred for 1 hour at r.t. Then 80 mL water and 80mL DCM were added, the organic phase extracted twice water and brine,combined aqueous phases were extracted twice with DCM, combined organicphases were dried over sodium sulfate, and evaporated. The resultingresidue was suspended in 5 mL DCM, filtered, the filtrate evaporated,suspended in 5 mL diethyl ether, filtered, and combined solids driedunder reduced pressure to yield 441 mg (1.3 mmol, 67%)3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dioneas an off-white solid.

ESI-MS [M+H]⁺ 345.3; LCMS Rt [min], meth. A: 0.61.

¹H-NMR (400 MHz, d₆-DMSO): δ (ppm)=8.20 (dd, J=7.9, 1.6 Hz, 1H),7.86-7.71 (m, 2H), 7.61-7.46 (m, 3H), 7.42-7.28 (m, 3H), 6.53 (s, 1H),3.90 (s, 3H), 2.48-2.41 (m, 1H), 1.18 (d, J=6.8 Hz, 6H).

The following examples can be made in a manner analogous to examples 1.1to 1.4:

The following examples were made in a manner analogous to examples 1.1to 1.4.

LCMS Rt [min], Ex Structure Name meth. A [M + H]⁺ 1.5 

8-fluoro-3-isopropyl-2- phenylbenzo[b][1,6] naphthyridine-1,10(2H,5H)-dione 0.67 349.1 1.6 

8-fluoro-3-isopropyl-5-methyl- 2-phenylbenzo[b][1,6] naphthyridine-1,10(2H,5H)-dione 0.59 363.2 1.7 

8-chloro-3-isopropyl-2- phenylbenzo[b][1,6] naphthyridine-1,10(2H,5H)-dione 0.61 365.1 1.8 

8-chloro-3-isopropyl-5- methyl-2- phenylbenzo[b][1,6] naphthyridine-1,10(2H,5H)-dione 0.61 379.1 1.9 

3-isopropyl-8-methyl-2- phenylbenzo[b][1,6] naphthyridine-1,10(2H,5H)-dione 0.60 345.2 1.10

3-isopropyl-5,8-dimethyl-2- phenylbenzo[b][1,6] naphthyridine-1,10(2H,5H)-dione 0.60 359.2 1.11

9-isopropyl-8-phenyl-1H- indolo[1,7- ab][1,6]naphthyridine-6,7(2H,8H)-dione 0.59 357.2 1.12

7-isopropyl-6- phenylthieno[2,3- b][1,6]naphthyridine- 4,5(6H,9H)-dione0.67 337.2 1.13

7-isopropyl-9-methyl-6- phenylthieno[2,3- b][1,6]naphthyridine-4,5(6H,9H)-dione 0.56 351.1 1.14

7-isopropyl-2-methyl-6- phenylthieno[2,3- b][1,6]naphthyridine-4,5(6H,9H)-dione 0.68 351.2 1.15

7-isopropyl-2,9-dimethyl-6- phenylthieno[2,3- b][1,6]naphthyridine-4,5(6H,9H)-dione 0.56 365.1 1.16

6-isopropyl-7- phenylthieno[3,2- b][1,6]naphthyridine- 8,9(4H,7H)-dione0.59 337.1 1.17

6-isopropyl-4-methyl-7- phenylthieno[3,2- b][1,6]naphthyridine-8,9(4H,7H)-dione 0.56 351.1 1.18

6-isopropyl-2-methyl-7- phenylthieno[3,2- b][1,6]naphthyridine-8,9(4H,7H)-dione 0.62 351.1 1.19

6-isopropyl-2,4-dimethyl-7- phenylthieno[3,2- b][1,6]naphthyridine-8,9(4H,7H)-dione 0.57 365.1 1.20

6-isopropyl-3-methyl-7- phenylthieno[3,2- b][1,6]naphthyridine-8,9(4H,7H)-dione 0.62 351.1 1.21

6-isopropyl-3,4-dimethyl-7- phenylthieno[3,2- b][1,6]naphthyridine-8,9(4H,7H)-dione 0.57 365.2 1.22

3-isopropyl-2-phenyl-6,7,8,9- tetrahydrobenzo[b][1,6] naphthyridine-1,10(2H,5H)-dione 0.56 335.2 1.23

3-isopropyl-2-phenyl-5,6,7,8- tetrahydro-1H- cyclopenta[b][1,6]naphthyridine-1,9(2H)-dione 0.59 321.2 1.24

3-cyclobutyl-5-methyl-2- phenyl-5,6,7,8-tetrahydro-1H-cyclopenta[b][1,6] naphthyridine-1,9(2H)-dione 0.50 347.3 1.25

7-cyclobutyl-1,2,3-trimethyl-6- phenyl-1,6-naphthyridine- 4,5(1H,6H)-dione 0.49 335.3 1.26

3-cyclobutyl-2-phenyl-5,6,7,8- tetrahydro-1H- cyclopenta[b][1,6]naphthyridine-1,9(2H)-dione 0.60 333.2 1.27

7-cyclobutyl-2,3-dimethyl-6- phenyl-1,6-naphthyridine- 4,5(1H,6H)-dione0.54 321.3 1.28

3-cyclobutyl-5-methyl-2- phenyl-6,7,8,9- tetrahydrobenzo[b][1,6]naphthyridine- 1,10(2H,5H)-dione 0.53 361.2 1.29

7-cyclobutyl-9-methyl-6- phenylthieno[2,3- b][1,6]naphthyridine-4,5(6H,9H)-dione 0.58 363.1 1.30

3-cyclobutyl-2-phenyl-6,7,8,9- tetrahydrobenzo[b][1,6] naphthyridine-1,10(2H,5H)-dione 0.56 347.2 1.31

7-cyclobutyl-2,9-dimethyl-6- phenylthieno[2,3- b][1,6]naphthyridine-4,5(6H,9H)-dione 0.59 377.3 1.32

7-cyclobutyl-6- phenylthieno[2,3- b][1,6]naphthyridine- 4,5(6H,9H)-dione0.68 349.1 1.33

7-cyclobutyl-2-methyl-6- phenylthieno[2,3- b][1,6]naphthyridine-4,5(6H,9H)-dione 0.70 363.1 1.34

6-cyclobutyl-4-methyl-7- phenylthieno[3,2- b][1,6]naphthyridine-8,9(4H,7H)-dione 0.58 363.4 1.35

6-cyclobutyl-7- phenylthieno[3,2- b][1,6]naphthyridine- 8,9(4H,7H)-dione0.61 349.1 1.36

6-cyclobutyl-2,4-dimethyl-7- phenylthieno[3,2- b][1,6]naphthyridine-8,9(4H,7H)-dione 0.59 377.2 1.37

6-cyclobutyl-2-methyl-7- phenylthieno[3,2- b][1,6]naphthyridine-8,9(4H,7H)-dione 0.62 363.1 1.38

3-cyclobutyl-5,8-dimethyl-2- phenylbenzo[b][1,6] naphthyridine-1,10(2H,5H)-dione 0.62 371.3 1.39

3-cyclobutyl-8-fluoro-5- methyl-2- phenylbenzo[b][1,6] naphthyridine-1,10(2H,5H)-dione 0.60 375.2 1.40

8-chloro-3-cyclobutyl-2- phenylbenzo[b][1,6] naphthyridine-1,10(2H,5H)-dione 0.63 377.1 1.41

3-cyclobutyl-8-methyl-2- phenylbenzo[b][1,6] naphthyridine-1,10(2H,5H)-dione 0.62 357.2 1.42

8-chloro-3-cyclobutyl-5- methyl-2- phenylbenzo[b][1,6] naphthyridine-1,10(2H,5H)-dione 0.63 391.2 1.43

3-isopropyl-6-methoxy-5- methyl-2- phenylbenzo[b][1,6] naphthyridine-1,10(2H,5H)-dione 0.61 375.2 1.44

3-cyclobutyl-8-fluoro-2- phenylbenzo[b][1,6] naphthyridine-1,10(2H,5H)-dione 0.62 361.1 1.45

9-cyclobutyl-8-phenyl-1H- indolo[1,7- ab][1,6]naphthyridine-6,7(2H,8H)-dione 0.63 369.1 1.46

3-cyclobutyl-6-methoxy-5- methyl-2- phenylbenzo[b][1,6] naphthyridine-1,10(2H,5H)-dione 0.66 387.1 1.47

3-isopropyl-6-methoxy-2- phenylbenzo[b][1,6] naphthyridine-1,10(2H,5H)-dione 0.61 361.2 1.48

3-cyclobutyl-6-methoxy-2- phenylbenzo[b][1,6] naphthyridine-1,10(2H,5H)-dione 0.64 373.1 1.49

3-isopropyl-8-methoxy-5- methyl-2- phenylbenzo[b][1,6] naphthyridine-1,10(2H(5H)-dione 0.63 375.2 1.50

3-isopropyl-8-methoxy-2- phenylbenzo[b][1,6] naphthyridine-1,10(2H,5H)-dione 0.63 361.1 1.51

8-hydroxy-3-isopropyl-5- methyl-2- phenylbenzo[b][1,6] naphthyridine-1,10(2H,5H)-dione 0.61 361.1 1.52

6-hydroxy-3-isopropyl-5- methyl-2- phenylbenzo[b][1,6] naphthyridine-1,10(2H,5H)-dione 0.63 361.1

Example 2.1:3-cyclobutyl-2-cyclopentylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione

a) 4-bromo-6-cyclobutyl-2H-pyran-2-one

To 400 mg (2.4 mmol) 6-cyclobutyl-4-hydroxy-2H-pyran-2-one (preparedaccording to example 1.1 b), 854 mg (2.7 mmol)tetrabutylammoniumbromide, and 752 mg (5.3 mmol) diphosphorus pentoxide8 mL toluene was added and the mixture was heated to 110° C. withvigorous stirring. At r.t. phases were separated, the aqueous phasetwice extracted with 4 mL toluene, combined organic phases washed with15 mL 20% aqueous (w/v) potassium bicarbonate solution and 15 mL brine,aqueous phases extracted with 5 mL toluene, combined organic phasesdried over sodium sulfate and evaporated to yield 507 mg (2.2 mmol, 92%)4-bromo-6-cyclobutyl-2H-pyran-2-one as a red oil.

b) Methyl 2-((6-cyclobutyl-2-oxo-2H-pyran-4-yl)amino)benzoate

Under argon 494 mg (2.2 mmol) 4-bromo-6-cyclobutyl-2H-pyran-2-one and1054 mg (3.2 mmol) caesium carbonate were suspended in 8 mL toluene andsubsequently 363 L (424 mg, 2.8 mmol) methyl 2-aminobenzoate, 16 mg(0.026 mmol) rac-BINAP, and 12 mg (0.013 mmol) Pd₂(dba)₃ were added. Themixture was heated to 110° C. for 23 hours. At r.t. the mixture wasfiltered through hyflo and the filtrate evaporated and purified byliquid chromatography over silica gel with cyclohexane/TBME as eluent.Target fractions were combined and evaporated to yield 458 mg (1.5 mmol,71%) methyl 2-((6-cyclobutyl-2-oxo-2H-pyran-4-yl)amino)benzoate as ayellow solid.

c) 3-cyclobutyl-1H-pyrano[4,3-b]quinoline-1,10(5H)-dione

To 0.4 g (1.4 mmol) methyl2-((6-cyclobutyl-2-oxo-2H-pyran-4-yl)amino)benzoate 5 g (1.4 mmol)polyphosphoric acid was added and heated to 130° C. for 45 minutes. Thereaction mixture was hydrolyzed with 20 mL water not exceeding r.t.,diluted with 40 mL water and neutralized to pH 7-8 by careful additionof solid potassium bicarbonate. The resulting solid was filtered, washedwith water and dried to yield 360 mg (1.4 mmol, 98%)3-cyclobutyl-1H-pyrano[4,3-b]quinoline-1,10(5H)-dione as off-whitesolid.

d)3-cyclobutyl-2-cyclopentylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione

To 329 mg (1.23 mmol)3-cyclobutyl-1H-pyrano[4,3-b]quinoline-1,10(5H)-dione in 6.2 mLtrifluoroethanol 850 μL (13.7 mmol) cyclopentylamine and 141 μL (5.5mmol) acetic acid were added and heated to 90° C. for 7 hours. Themixture was evaporated, the residue twice mixed with 4 mL ethylether andfiltered, washed twice with 7.5 mL isopropanol/diethylether 3:2 (v/v),with 7 mL diethylether and eight times thoroughly with water. Theremaining solid was dried to yield 373 mg (1.1 mmol, 91%)3-cyclobutyl-2-cyclopentylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dioneas an off-white solid.

ESI-MS [M+H]⁺ 335.1; LCMS Rt [min], meth. A: 0.66;

¹H-NMR (400 MHz, d₆-DMSO): δ (ppm)=11.58 (s, 1H), 8.09 (dd, J=8.0, 1.2Hz, 1H), 7.64 (dt, 1H), 7.41 (dd, J=8.1 Hz, 1H), 7.27 (dt, J=7.5 Hz,1H), 6.08 (s, 1H), 4.43 (p, 1H), 3.71 (p, 1H), 2.41-2.26 (m, 2H),2.26-2.07 (m, 4H), 2.07-1.89 (m, 3H), 1.89-1.63 (m, 3H), 1.63-1.41 (m,2H)

Example 2.2:3-cyclobutyl-2-cyclopentyl-5-methylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione

Preparation according to example 1.2 starting with 129 mg (0.38 mmol)3-cyclobutyl-2-cyclopentylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione(example 2.1) to yield 121 mg (0.35, 90%)3-cyclobutyl-2-cyclopentyl-5-methylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dioneas an off-white solid.

ESI-MS [M+H]⁺ 349.2; LCMS Rt [min], meth. A: 0.70;

¹H-NMR (400 MHz, d₆-DMSO): δ (ppm)=8.20 (dd, J=7.9, 1.4 Hz, 1H), 7.78(dd, J=8.3 Hz, 1H), 7.72 (dt, J=8.6, 1.6 Hz, 1H), 7.35 (dt, J=7.3 Hz,1H), 6.23 (s, 1H), 4.49 (p, J=8.6 Hz, 1H), 3.76 (p, J=8.6 Hz, 1H),2.45-2.33 (m, 2H), 2.33-2.25 (m, 2H), 2.20 (m, J=14.8, 7.4 Hz, 2H),2.11-1.90 (m, 3H), 1.90-1.66 (m, 3H), 1.66-1.48 (m, 2H)

Example 2.3:2-cyclopentyl-3-isopropylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione

Preparation according to example 2.1 a) to d) using 243 mg (0.95 mmol)3-isopropyl-1H-pyrano[4,3-b]quinoline-1,10(5H)-dione to yield 220 mg(0.68 mmol, 72%)2-cyclopentyl-3-isopropylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione asa white solid.

ESI-MS [M+H]⁺ 323.2; LCMS Rt [min], meth. A: 0.64.

¹H-NMR (400 MHz, d₆-DMSO): δ (ppm)=11.55 (s, 1H), 8.09 (dd, J=7.9 Hz,1H), 7.64 (dt, J=7.5 Hz, 1H), 7.41 (dd, J=8.1 Hz, 1H), 7.26 (dt, J=7.5Hz, 1H), 6.13 (s, 1H), 4.74 (p, 1H), 3.24 (hept, J=6.5 Hz, 1H),2.29-2.13 (m, 2H), 2.01 (m, 2H), 1.88-1.72 (m, 2H), 1.68-1.52 (m, 2H),1.28 (m, J=6.5 Hz, 6H)

Example 2.4:2-cyclopentyl-3-isopropyl-5-methylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione

Preparation according to example 2.2 using 33 mg (0.1 mmol)2-cyclopentyl-3-isopropylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione toyield 26 mg (0.08 mmol, 76%)2-cyclopentyl-3-isopropyl-5-methylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dioneas off-white solid.

ESI-MS [M+H]⁺ 337.1; LCMS Rt [min], meth. A: 0.64;

¹H-NMR (400 MHz, d₆-DMSO): δ (ppm)=8.20 (dd, 1H), 7.77 (dd, J=8.1 Hz,1H), 7.73 (dt, 1H), 7.35 (dt, 1H), 6.33 (s, 1H), 4.80 (p, J=8.5 Hz, 1H),3.82 (s, 3H), 3.30 (hept, 1H), 2.28-2.13 (m, 2H), 2.09-1.95 (m, 2H),1.88-1.74 (m, 2H), 1.68-1.53 (m, 2H), 1.34 (m, J=6.7 Hz, 6H)

Example 2.5:3-cyclobutyl-2-(pyridin-2-yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dione

Preparation according to example 2.1 reacting 219 mg (0.82 mmol)3-cyclobutyl-1H-pyrano[4,3-b]quinoline-1,10(5H)-dione and 769 mg (8.2mmol) 2-aminopyridine without solvent at 170° C. for 17 hours to yield209 mg (0.61 mmol, 75%)3-cyclobutyl-2-(pyridin-2-yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dioneas brownish solid.

ESI-MS [M+H]⁺ 344.3; LCMS Rt [min], meth. A: 0.57;

¹H-NMR (400 MHz, d₆-DMSO): δ (ppm)=11.82 (s, 1H), 8.68-8.58 (m, 1H),8.11 (dd, 1H), 8.01 (dt, J=7.7, 1.9 Hz, 1H), 7.69 (dt, 1H), 7.53 (dd,J=6.7, 5.0 Hz, 1H), 7.50-7.42 (m, 2H), 7.32 (t, J=7.5 Hz, 1H), 6.22 (s,1H), 3.22 (p, J=9.0 Hz, 1H), 2.14-1.41 (m, 6H)

Example 2.6:3-cyclobutyl-5-methyl-2-(pyridin-2-yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dione

Preparation according to example 2.2 reacting 100 mg (0.29 mmol)3-cyclobutyl-2-(pyridin-2-yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dioneto yield 68 mg (0.19 mmol, 66%)3-cyclobutyl-5-methyl-2-(pyridin-2-yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dioneas

ESI-MS [M+H]⁺: 358.1; LCMS Rt [min], meth. A: 0.57;

¹H-NMR (400 MHz, d₆-DMSO): δ (ppm)=8.64 (dd, 1H), 8.22 (dd, J=7.9, 1.4Hz, 1H), 8.03 (dt, J=7.7, 1.8 Hz, 1H), 7.85 (d, J=8.6 Hz, 1H), 7.78 (dt,1H), 7.55 (dd, J=7.1, 5.2 Hz, 1H), 7.47 (d, J=7.9 Hz, 1H), 7.40 (t,J=7.4 Hz, 1H), 6.43 (s, 1H), 3.93 (s, 3H), 3.25 (dt, J=17.3, 8.4 Hz,1H), 2.15 (s, 2H), 1.78-1.47 (m, 4H).

Example 2.7:3-cyclobutyl-2-(pyrrolidin-1-yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dione

Preparation according to example 2.1 using 247 mg (0.92 mmol)3-cyclobutyl-1H-pyrano[4,3-b]quinoline-1,10(5H)-dione and 588 mg (3.7mmol) 1-aminopyrrolidine in 5 mL DMA at 170° C. for 12 hours to yield255 mg (0.76 mmol, 82%)3-cyclobutyl-2-(pyrrolidin-1-yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dioneas off-white solid.

ESI-MS [M+H]⁺ 336.2; LCMS Rt [min], meth. A: 0.67

¹H-NMR (400 MHz, d₆-DMSO): δ (ppm)=11.67 (s, 1H), 8.10 (dd, 1H), 7.66(dt, 1H), 7.43 (dd, J=8.1 Hz, 1H), 7.29 (dt, 1H), 6.05 (s, 1H), 3.70 (p,J=8.8 Hz, 1H), 3.48 (q, J=7.1, 6.7 Hz, 2H), 3.07 (q, 2H), 3.02-2.92 (m,2H), 2.37-1.73 (m, 10H)

Example 2.8:3-cyclobutyl-5-methyl-2-(pyrrolidin-1-yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dione

Preparation according to example 2.2 reacting 124 mg (0.37 mmol)3-cyclobutyl-2-(pyrrolidin-1-yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dioneto yield 72.3 mg (0.19 mmol, 52%)3-cyclobutyl-5-methyl-2-(pyrrolidin-1-yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dioneas

ESI-MS [M+H]⁺ 350.1; LCMS Rt [min], meth. A: 0.67.

¹H-NMR (400 MHz, d₆-DMSO): δ (ppm)=8.20 (dd, J=7.9, 1.4 Hz, 1H), 7.80(dd, J=8.5 Hz, 1H), 7.74 (dt, 1H), 7.37 (dt, J=7.3 Hz, 1H), 6.22 (s,1H), 3.85 (s, 3H), 3.77 (p, J=9.0 Hz, 1H), 3.49 (q, J=7.2 Hz, 2H), 2.98(q, J=7.3 Hz, 2H), 2.37-1.74 (m, 10H).

The following examples were made in a manner analogous to examples 2.1to 2.8.

LCMS Rt [min], Ex Structure Name meth. A [M + H]⁺ 2.9 

3-isopropyl-2-(pyridin-2- yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dione 0.56 332.1 2.10

3-isopropyl-5-methyl-2- (pyridin-2- yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dione 0.56 346.1 2.11

3-isopropyl-2-(pyrrolidin-1- yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dione 0.66 324.1 2.12

3-isopropyl-5-methyl-2- (pyrrolidin-1- yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dione 0.66 338.1 2.13

3-isopropyl-2-(piperidin-1- yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dione 0.73 338.2 2.14

3-isopropyl-5-methyl-2- (piperidin-1- yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dione 0.67 352.2 2.15

6-cyclopentyl-7- isopropylthieno[2,3- b][1,6]naphthyridine-4,5(6H,9H)-dione 0.76 329.1 2.16

6-cyclopentyl-7-isopropyl-9- methylthieno[2,3- b][1,6]naphthyridine-4,5(6H,9H)-dione 0.59 343.1 2.17

3-isopropyl-2-(1H-pyrrol-1- yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dione 0.60 320.1 2.18

3-isopropyl-5-methyl-2-(1H- pyrrol-1- yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dione 0.59 334.1

Example 3.1:4-chloro-3-isopropyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione

To a suspension of 50 mg (0.15 mmol)3-isopropyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione(example 1.3) and 1 mg (7.6 μmol) aluminum trichloride in 1 mL pyridineand 0.43 mL acetic acid 20 mg (0.15 mmol) 1-chloropyrrolidine-2,5-dionewas added in portions over 5 minutes and the mixture was stirred at 50°C. over 3 hours.

The reaction mixture was cooled to r.t., diluted with 3 mL water andstirred for one hour. The solid was filtered off, washed with water anddried to yield 40 mg (0.1 mmol, 69%)4-chloro-3-isopropyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dioneas a yellow powder.

ESI-MS [M+H]⁺ 365.0; LCMS Rt [min], meth. A: 0.64;

¹H-NMR (400 MHz, d₆-DMSO): δ (ppm)=10.90 (s, 1H), 8.14-8.05 (m, 2H),7.75-7.68 (m, 1H), 7.60-7.50 (m, 3H), 7.40-7.31 (m, 3H), 2.81 (bs, 1H),1.30 (d, J=7.1 Hz, 6H).

Example 3.2:4-chloro-3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione

The compound was prepared starting from 100 mg (0.29 mmol)3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione(example 1.4) under the reaction conditions described for example 3.1 toyield 20 mg (53 mol, 18%)4-chloro-3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dioneas off-white solid.

ESI-MS [M+H]⁺ 379.2; LCMS Rt [min], meth. A: 0.66;

¹H-NMR (400 MHz, d₆-DMSO): δ (ppm)=8.15-8.09 (m, 1H), 7.83-7.73 (m, 2H),7.61-7.54 (m, 2H), 7.54-7.48 (m, 1H), 7.45-7.38 (m, 1H), 7.38-7.33 (m,2H), 3.92 (s, 3H), 3.18 (d, J=3.8 Hz, 1H), 2.81 (bs, 1H), 1.30 (d, J=7.2Hz, 6H).

Example 3.3:4-bromo-3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione

The compound was prepared starting from 1.0 g (2.9 mmol)3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione(example 1.4) under the reaction conditions described for example 3.1using 1.03 g (5.8 mmol) 1-bromopyrrolidine-2,5-dione, 20 mg (0.15 mmol)aluminum trichloride and mL acetic acid in 20 mL pyridine to yield 1.05g (2.35 mmol, 81%)4-bromo-3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dioneas an off-white solid.

ESI-MS [M+H]⁺ 423.1; LCMS Rt [min], meth. A: 0.67;

¹H-NMR (400 MHz, d₆-DMSO): δ (ppm)=8.15-8.08 (m, 1H), 7.82-7.75 (m, 2H),7.61-7.48 (m, 3H), 7.44-7.38 (m, 1H), 7.38-7.33 (m, 2H), 3.93 (s, 3H),2.93 (bs, 1H), 1.30 (bd, J=7.5 Hz, 6H).

Biological Testing

In-Vitro Testing: CFTR-Y122X Assay

Activity of compounds of the present invention was examined inrecombinant, dual reporter isogenic Hek293 cell lines (“CFTR-Y122Xassay”). The engineered reporter constructs contained the 18 bp sequencestrech corresponding to a common Y122X PTC mutation in CFTR class Imutant patients (see Sermet-Gaudelus, BMC Medicine, 2007, 5(5)). Insteadof a tyrosine (Y) in position 122 of the CFTR protein a TGA stop codoninterrupts the open reading frame (Y122X) of the corresponding mRNA.This TGA stop codon triplet (followed by the pyrimidine base cytosine)is permissive to aminoglycoside mediated translational readthrough whichserved as positive control for high throughput screening. Acorresponding TAA stop codon variant and a wildtype non mutatedconstruct was used for confirmation and counter screening. The CFTRsequence was sandwiched between an eGFP reporter, and a triple myc tagsequence fused to a full length Renilla reporter. All sequences,including an intron containing one positioned pre-eGFP (b-globin intron)were cloned in frame. The corresponding expression constructs werestably expressed in the isogenic HEK-R4 cell host (Invitrogen Incorp.)and selected by blasticidin resistance. The isogenic integration of theconstruct minimizes gene dose effects and improves assayreproducibility. Stably integrated single cell derived clones wereselected and characterized for aminoglycoside mediated readthrough. Aclone with optimal growth characteristics and strong response (EC₅₀ of1.5 mM) to paromomycin was pursued for HTS assay development.Readthrough of Y122X accumulates an intracellular localized fusionprotein approximately 65.5 kDa in size as controlled by western blotanalysis and immunofluorescence using an anti-renilla antibody. The eGFPreporter pre-PTC mutation serves as visual control for genetic stabilityof the screening clones and minimizes protein degradation of smallfusion protein amounts. In the assay, compound concentration was 10 μM.In miniaturized 1536 well format 2000 cells were dispensed in 4 μl/welland incubated for 24 h at 37° C., 5% CO₂. 40 nl compounds were placed onthe cells with control wells containing 1 ul Paramomycin and 14.4 mMfinal concentration. Compounds were incubated for 24 h. Renilla Glosubstrate (2.5 ul) was added and plates were centrifuged and processedfor luminescence measurement using various readers. Activity calculationwas done using the equation: A1(%)=100*(S−NC)/(AC−NC) where AC, NC and Scorrespond to active controls (injection of Stimulation buffer=100%stimulation), neutral controls (buffer injection which Iloprost EC10)and screening samples (S). NC corresponds to 0% activity whereas AC is100% activity (14 mM paromomycin). False positive artefacts were removedin confirmation and validation screening using the same assay formatfollowed by counterscreening using the respective wildtype construct(w/o PTC mutation) cell model. Compounds were tested up to 100 μMcompound concentration.

TABLE 2 In-vitro activity in CFTR-Y122X assay: Table 2 represents AC₅₀values for nonsense mutation suppression in the CFTR-Y122X assay.A_(max) AC₅₀ Ex [%] [μM] 1.1 219 0.6 1.2 260 1.0 1.3 281 1.1 1.4 324 3.21.5 358 1.8 1.6 507 7.7 1.7 215 2.4 1.8 307 14.8 1.9 249 1.2 1.10 4097.3 1.11 276 4.0 1.12 248 19.0 1.13 445 8.6 1.14 35 —* 1.15 224 5.5 1.16344 1.6 1.17 430 9.2 1.18 240 3.9 1.19 253 12.8 1.20 183 2.5 1.21 3795.4 1.22 413 7.2 1.23 414 5.2 1.24 157 18.4 1.25 87 16.8 1.26 229 3.31.27 206 3.0 1.28 257 12.8 1.29 286 0.7 1.30 324 0.7 1.31 228 0.6 1.32247 4.2 1.33 243 19.4 1.34 263 1.0 1.35 126 0.4 1.36 177 4.1 1.37 1641.4 1.38 215 2.3 1.39 239 1.2 1.40 300 1.0 1.41 223 0.5 1.42 134 3.91.43 186 22 1.44 178 0.4 1.45 252 0.6 1.46 247 3.4 1.47 312 5.2 1.48 2271.8 1.49 17 —* 1.50 110 16.9 1.51 144 16.5 1.52 49 21 2.1 229 0.5 2.2262 2.1 2.3 235 0.4 2.4 274 1.8 2.5 217 2.7 2.6 232 3.3 2.7 197 0.7 2.8188 6.1 2.9 198 4.2 2.10 177 10.0 2.11 2026 0.9 2.12 178 1.7 2.13 2651.8 2.14 271 1.7 2.15 124 —* 2.16 279 1.2 2.17 237 9.0 2.18 75 17.6 3.1211 3.2 3.2 220 17.2 3.3 122 18.8 *not determined

Table 2 shows that compounds of formula (I′) show activity in afunctional assay indicating they promote translational readthrough.

The following compounds of formula (I′) were tested in the abovedescribed CFTR-Y122X assay at the above dose ranges and suppressionreaching only less than 5% of paromomycin reference activity was seen:

-   7-isopropyl-3-methyl-6-phenylthieno[2,3-b][1,6]naphthyridine-4,5(6H,9H)-dione;-   7-isopropyl-3,9-dimethyl-6-phenylthieno[2,3-b][1,6]naphthyridine-4,5(6H,9H)-dione.

In an embodiment of the invention, the compound of the invention is not

-   7-isopropyl-3-methyl-6-phenylthieno[2,3-b][1,6]naphthyridine-4,5(6H,9H)-dione-   7-isopropyl-3,9-dimethyl-6-phenylthieno[2,3-b][1,6]naphthyridine-4,5(6H,9H)-dione.

The invention claimed is:
 1. A compound of formula (Ia′) in free form orin pharmaceutically acceptable salt form, wherein:

R₁ is selected from a five- to seven-membered monocyclic saturated orunsaturated non-aromatic ring system, wherein said ring system maycontain from 1 to 4 hetero atoms selected from nitrogen, oxygen andsulfur, and wherein said ring system may be substituted once or morethan once by R₆; pyrrolyl; pyrazolyl; thiophenyl; and pyridin-2-yl; and

wherein the phenyl ring is attached via the bond marked with an asterisk(*), and wherein the pyrrolyl, pyrazolyl, thiophenyl, and pyridin-2-ylmay be substituted by C₁₋₃alkyl; wherein when R₁ is a five- toseven-membered monocyclic saturated or unsaturated non-aromatic ringsystem, then R₂ is selected from C₂₋₆alkyl which may be substituted onceor more than once by R₇; —X₁—R₈; and a three- to seven-memberedmonocyclic aromatic, saturated or unsaturated non-aromatic ring system,wherein said ring system may contain from 1 to 4 hetero atoms selectedfrom nitrogen, oxygen and sulfur, and wherein said ring system may besubstituted once or more than once by R₁₁; or wherein when R₁ ispyrrolyl, pyrazolyl, thiophenyl, pyridin-2-yl, or phenyl, then R₂ isselected from C₂₋₇alkyl which may be substituted once or more than onceby R₁₃; —X₂—R₁₄; and a three- to seven-membered monocyclic saturated orunsaturated non-aromatic ring system, wherein said ring system maycontain from 1 to 4 hetero atoms selected from nitrogen, oxygen andsulfur, and wherein said ring system may be substituted once or morethan once by R₁₇; X₁— is —O—, —S— or —N(R₉)—; X₂— is —O—, —S— or—N(R₁₅)—; R₃ is hydrogen or —CH₂R₁₈; R₈ is C₁₋₆alkyl which may besubstituted once or more than once by R₁₀; R₉ is hydrogen or C₁₋₄alkyl;each R₁₂ independently is hydrogen, halogen, hydroxyl, amino, cyano,nitro, C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄hydroxyalkyl,C₁₋₄alkoxy-C₁₋₄alkyl, amino-C₁₋₄alkyl, C₁₋₄alkyl-amino-C₁₋₄alkyl,di(C₁₋₄alkyl)-amino-C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄halogenalkoxy,C₁₋₄alkylamino or di(C₁₋₄alkyl)amino; or C₃₋₆cycloalkyl, wherein onecarbon atom may be replaced by an oxygen atom, wherein theC₃₋₆cycloalkyl may be attached directly or via a C₁₋₂alkylene, andwherein the C₃₋₆cycloalkyl may be substituted once or more than once byhalogen; R₁₄ is C₁₋₆alkyl which may be substituted once or more thanonce by R₁₆; R₁₅ is hydrogen or C₁₋₄alkyl; R₁₈ is hydrogen, C₁₋₄alkyl,C₂₋₆alkenyl, C₃₋₆cycloalkyl, C₁₋₃alkoxyC₁₋₃alkyl, hydroxyC₁₋₃alkyl oraminoC₁₋₃alkyl; R₂₁ is hydrogen, halogen, hydroxyl, amino, cyano,C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy-C₁₋₄alkyl,amino-C₁₋₄alkyl, C₁₋₄alkyl-amino-C₁₋₄alkyl,di(C₁₋₄alkyl)-amino-C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄halogenalkoxy,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino; or a three- to seven-memberedmonocyclic aromatic, saturated or unsaturated non-aromatic ring system,wherein said ring system may contain from 1 to 4 hetero atoms selectedfrom nitrogen, oxygen and sulfur, wherein said ring system may beattached directly or via a C₁₋₂alkylene, and wherein said ring systemmay be substituted once or more than once by R₂₃; R₂₂ is hydrogen,halogen, hydroxyl, cyano, C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄hydroxyalkyl,C₁₋₄alkoxy-C₁₋₄alkyl, amino-C₁₋₄alkyl, C₁₋₄alkyl-amino-C₁₋₄alkyl,di(C₁₋₄alkyl)-amino-C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkinyl, C₁₋₄alkoxy,C₁₋₄halogenalkoxy, or C₃₋₄cycloalkyl, wherein one carbon atom of theC₃₋₄cycloalkyl may be replaced by an oxygen atom, wherein theC₃₋₄cycloalkyl may be attached directly or via a C₁₋₂alkylene, andwherein the C₃₋₄cycloalkyl may be substituted once or more than once byhalogen; R₆, R₁₁, R₁₇, and R₂₃ each independently is halogen, hydroxyl,amino, cyano, nitro, C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄hydroxyalkyl,C₁₋₄alkoxy-C₁₋₄alkyl, amino-C₁₋₄alkyl, C₁₋₄alkyl-amino-C₁₋₄alkyl,di(C₁₋₄alkyl)-amino-C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄halogenalkoxy,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, or C₃₋₆cycloalkyl, wherein onecarbon atom of the C₃₋₆cycloalkyl may be replaced by an oxygen atom,wherein the C₃₋₆cycloalkyl may be attached directly or via aC₁₋₂alkylene, and wherein the C₃₋₆cycloalkyl may be substituted once ormore than once by halogen; or two R₆, R₁₁, R₁₇, and R₂₃ at the same ringatom together are oxo; or two R₆, R₁₁, R₁₇, and R₂₃ at the same ringcarbon atom together with said carbon atom form a C₃₋₆cycloalkyl; R₇,R₁₀, R₁₃, and R₁₆ each independently is halogen, hydroxyl, amino, cyano,nitro, C₁₋₄alkoxy, C₁₋₄halogenalkoxy, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, or C₃₋₆cycloalkyl, wherein one carbon atom of theC₃₋₆cycloalkyl may be replaced by an oxygen atom, wherein theC₃₋₆cycloalkyl may be attached directly or via a C₁₋₂alkylene, andwherein the C₃₋₆cycloalkyl may be substituted once or more than once byhalogen; or two R₇, R₁₀, R₁₃, or R₁₆ at the same carbon atom togetherare oxo; or two R₇, R₁₀, R₁₃, or R₁₆ at the same carbon atom togetherwith said carbon atom form a C₃₋₆cycloalkyl; and R₂₄ is hydrogen orhalogen.
 2. A compound of formula (Ia′) in free form or in apharmaceutically acceptable salt form according to claim 1, wherein: R₁is phenyl; R₁₂ for each occurrence is hydrogen; and R₂ is selected fromC₂₋₇alkyl which may be substituted once or more than once by R₁₃; and athree- to seven-membered monocyclic saturated or unsaturatednon-aromatic ring system, wherein said ring system may contain from 1 to4 hetero atoms selected from nitrogen, oxygen and sulfur, and whereinsaid ring system may be substituted once or more than once by R₁₇.
 3. Acompound of formula (Ia′) in free form or in a pharmaceuticallyacceptable salt form according to claim 1, wherein: R₁ is a ringselected from pyrazolyl, thiophenyl and pyridin-2-yl, which ring may besubstituted by C₁₋₃alkyl; and R₂ is selected from C₂₋₇alkyl which may besubstituted once or more than once by R₁₃; and a three- toseven-membered monocyclic saturated or unsaturated non-aromatic ringsystem, wherein said ring system may contain from 1 to 4 hetero atomsselected from nitrogen, oxygen and sulfur, and wherein said ring systemmay be substituted once or more than once by R₁₇.
 4. A compound offormula (Ia′) in free form or in a pharmaceutically acceptable salt formaccording to claim 1, wherein: R₁ is a five- to seven-memberedmonocyclic saturated or unsaturated non-aromatic ring system, whereinsaid ring system may contain from 1 to 4 hetero atoms selected fromnitrogen, oxygen and sulfur, and wherein said ring system may besubstituted once or more than once by R₆; and R₂ is selected fromC₂₋₆alkyl which may be substituted once or more than once by R₇ and athree- to seven-membered monocyclic aromatic, saturated or unsaturatednon-aromatic ring system, wherein said ring system may contain from 1 to4 hetero atoms selected from nitrogen, oxygen and sulfur, and whereinsaid ring system may be substituted once or more than once by R₁₁.
 5. Acompound in free form or in pharmaceutically acceptable salt form, whichis selected from:3-cyclobutyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;3-cyclobutyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;3-isopropyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;8-fluoro-3-isopropyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;8-fluoro-3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;8-chloro-3-isopropyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;8-chloro-3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;3-isopropyl-8-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;3-isopropyl-5,8-dimethyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;9-isopropyl-8-phenyl-1H-indolo[1,7-ab][1,6]naphthyridine-6,7(2H,8H)-dione;7-isopropyl-6-phenylthieno[2,3-b][1,6]naphthyridine-4,5(6H,9H)-dione;7-isopropyl-9-methyl-6-phenylthieno[2,3-b][1,6]naphthyridine-4,5(6H,9H)-dione;7-isopropyl-2-methyl-6-phenylthieno[2,3-b][1,6]naphthyridine-4,5(6H,9H)-dione;7-isopropyl-2,9-dimethyl-6-phenylthieno[2,3-b][1,6]naphthyridine-4,5(6H,9H)-dione;6-isopropyl-7-phenylthieno[3,2-b][1,6]naphthyridine-8,9(4H,7H)-dione;6-isopropyl-4-methyl-7-phenylthieno[3,2-b][1,6]naphthyridine-8,9(4H,7H)-dione;6-isopropyl-2-methyl-7-phenylthieno[3,2-b][1,6]naphthyridine-8,9(4H,7H)-dione;6-isopropyl-2,4-dimethyl-7-phenylthieno[3,2-b][1,6]naphthyridine-8,9(4H,7H)-dione;6-isopropyl-3-methyl-7-phenylthieno[3,2-b][1,6]naphthyridine-8,9(4H,7H)-dione;6-isopropyl-3,4-dimethyl-7-phenylthieno[3,2-b][1,6]naphthyridine-8,9(4H,7H)-dione;3-isopropyl-2-phenyl-6,7,8,9-tetrahydrobenzo[1,6]naphthyridine-1,10(2H,5H)-dione;3-isopropyl-2-phenyl-5,6,7,8-tetrahydro-1H-cyclopenta[b][1,6]naphthyridine-1,9(2H)-dione;3-cyclobutyl-5-methyl-2-phenyl-5,6,7,8-tetrahydro-1H-cyclopenta[b][1,6]naphthyridine-1,9(2H)-dione;3-cyclobutyl-2-phenyl-5,6,7,8-tetrahydro-1H-cyclopenta[b][1,6]naphthyridine-1,9(2H)-dione;3-cyclobutyl-5-methyl-2-phenyl-6,7,8,9-tetrahydrobenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;7-cyclobutyl-9-methyl-6-phenylthieno[2,3-b][1,6]naphthyridine-4,5(6H,9H)-dione;7-cyclobutyl-2,9-dimethyl-6-phenylthieno[2,3-b][1,6]naphthyridine-4,5(6H,9H)-dione;7-cyclobutyl-6-phenylthieno[2,3-b][1,6]naphthyridine-4,5(6H,9H)-dione;7-cyclobutyl-2-methyl-6-phenylthieno[2,3-b][1,6]naphthyridine-4,5(6H,9H)-dione;6-cyclobutyl-4-methyl-7-phenylthieno[3,2-b][1,6]naphthyridine-8,9(4H,7H)-dione;6-cyclobutyl-7-phenylthieno[3,2-b][1,6]naphthyridine-8,9(4H,7H)-dione;6-cyclobutyl-2,4-dimethyl-7-phenylthieno[32-b][1,6]naphthyridine-8,9(4H,7H)-dione;6-cyclobutyl-2-methyl-7-phenylthieno[3,2-b][1,6]naphthyridine-8,9(4H,7H)-dione;3-cyclobutyl-5,8-dimethyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;3-cyclobutyl-8-fluoro-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;8-chloro-3-cyclobutyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;3-cyclobutyl-8-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;8-chloro-3-cyclobutyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;3-isopropyl-6-methoxy-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;3-cyclobutyl-8-fluoro-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;9-cyclobutyl-8-phenyl-1H-indolo[1,7-ab][1,6]naphthyridine-6,7(2H,8H)-dione;3-cyclobutyl-6-methoxy-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;3-isopropyl-6-methoxy-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;3-cyclobutyl-6-methoxy-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;3-isopropyl-8-methoxy-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;3-isopropyl-8-methoxy-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;8-hydroxy-3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;6-hydroxy-3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;3-cyclobutyl-2-cyclopentylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;3-cyclobutyl-2-cyclopentyl-5-methylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;2-cyclopentyl-3-isopropylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;2-cyclopentyl-3-isopropyl-5-methylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;3-cyclobutyl-2-(pyridin-2-yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;3-cyclobutyl-5-methyl-2-(pyridin-2-yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;3-cyclobutyl-2-(pyrrolidin-1-yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;3-cyclobutyl-5-methyl-2-(pyrrolidin-1-yl)benzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;4-chloro-3-isopropyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;4-chloro-3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;and4-bromo-3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione.6. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound according to claim 1 and one or morepharmaceutically acceptable carriers.
 7. A compound in free form or inpharmaceutically acceptable salt form selected from the group consistingof: 3-cyclobutyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-di one;3-isopropyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;3-cyclobutyl-2-cyclopentyl-5-methylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione;2-cyclopentyl-3-isopropylbenzo[b][1,6]naphthyridine-1,10(2H, 5H)-dione;and2-cyclopentyl-3-isopropyl-5-methylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione.8. A compound in free form or in pharmaceutically acceptable salt formaccording to claim 7 which is3-cyclobutyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione.
 9. A compound in free form or in pharmaceutically acceptable saltform according to claim 7 which is3-isopropyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione.
 10. Acompound in free form or in pharmaceutically acceptable salt formaccording to claim 7 which is3-isopropyl-5-methyl-2-phenylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione.11. A compound in free form or in pharmaceutically acceptable salt formaccording to claim 7 which is3-cyclobutyl-2-cyclopentyl-5-methylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione.12. A compound in free form or in pharmaceutically acceptable salt formaccording to claim 7 which is2-cyclopentyl-3-isopropylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione.13. A compound in free form or in pharmaceutically acceptable salt formaccording to claim 7 which is2-cyclopentyl-3-isopropyl-5-methylbenzo[b][1,6]naphthyridine-1,10(2H,5H)-dione.14. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound according to claim 7 and one or morepharmaceutically acceptable carriers.